Advertisement

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

  • Philipp Klahn
  • Mark Brönstrup
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 398)

Abstract

The development of bacterial resistance against current antibiotic drugs necessitates a continuous renewal of the arsenal of efficacious drugs. This imperative has not been met by the output of antibiotic research and development of the past decades for various reasons, including the declining efforts of large pharma companies in this area. Moreover, the majority of novel antibiotics are chemical derivatives of existing structures that represent mostly step innovations, implying that the available chemical space may be exhausted. This review negates this impression by showcasing recent achievements in lead finding and optimization of antibiotics that have novel or unexplored chemical structures. Not surprisingly, many of the novel structural templates like teixobactins, lysocin, griselimycin, or the albicidin/cystobactamid pair were discovered from natural sources. Additional compounds were obtained from the screening of synthetic libraries and chemical synthesis, including the gyrase-inhibiting NTBI’s and spiropyrimidinetrione, the tarocin and targocil inhibitors of wall teichoic acid synthesis, or the boronates and diazabicyclo[3.2.1]octane as novel β-lactamase inhibitors. A motif that is common to most clinically validated antibiotics is that they address hotspots in complex biosynthetic machineries, whose functioning is essential for the bacterial cell. Therefore, an introduction to the biological targets—cell wall synthesis, topoisomerases, the DNA sliding clamp, and membrane-bound electron transport—is given for each of the leads presented here.

Keywords

Wall Teichoic Acid ADMET Property Antibacterial Target Antibiotic Research Division Septum 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank Dr. Dr. Werner Tegge, Giambattista Testolin, Isabell Schneider and Dr. Verena Fetz for fruitful discussions and for proofreading of the manuscript.

References

  1. Aguilaniu H, Durieux J, Dillin A (2005) Metabolism, ubiquinone synthesis, and longevity. Genes Dev 19:2399–2406. doi: 10.1101/gad.1366505 PubMedCrossRefGoogle Scholar
  2. Aldred KJ, Kerns RJ, Osheroff N (2014) Mechanism of quinolone action and resistance. Biochemistry 53:1565–1574. doi: 10.1021/bi5000564 PubMedPubMedCentralCrossRefGoogle Scholar
  3. Alm RA, Lahiri SD, Kutschke A et al (2015) Characterization of the novel DNA gyrase inhibitor AZD0914: low resistance potential and lack of cross-resistance in Neisseria gonorrhoeae. Antimicrob Agents Chemother 59:1478–1486. doi: 10.1128/AAC.04456-14 PubMedPubMedCentralCrossRefGoogle Scholar
  4. Amaral L, Martins A, Spengler G, Molnar J (2014) Efflux pumps of Gram-negative bacteria: what they do, how they do it, with what and how to deal with them. Front Pharmacol 4:Article168. doi: 10.3389/fphar.2013.00168
  5. Anderson VE, Osheroff N (2001) Type II topoisomerases as targets for quinolone antibacterials: turning Dr. Jekyll into Mr. Hyde. Curr Pharm Des 7:337–353. doi: 10.2174/1381612013398013 PubMedCrossRefGoogle Scholar
  6. Anderson RJ, Groundwater PW, Todd A, Worsley AJ (2012) Antibacterial agents: chemistry, mode of action, mechanisms of resistance and clinical applications. Wiley, New YorkCrossRefGoogle Scholar
  7. Argiriadi MA, Goedken ER, Bruck I, et al (2006) Crystal structure of a DNA polymerase sliding clamp from a Gram-positive bacterium. BMC Struct Biol 6:2. doi: 10.1186/1472-6807-6-2
  8. Askoura M, Mottawea W, Abujamel T, Taher I (2011) Efflux pump inhibitors (EPIs) as new antimicrobial agents against Pseudomonas aeruginosa. Libyan J Med 6:1–8. doi: 10.3402/ljm.v6i0.5870 CrossRefGoogle Scholar
  9. Atilano ML, Pereira PM, Yates J et al (2010) Teichoic acids are temporal and spatial regulators of peptidoglycan cross-linking in Staphylococcus aureus. Proc Natl Acad Sci USA 107:18991–18996. doi: 10.1073/pnas.1004304107 PubMedPubMedCentralCrossRefGoogle Scholar
  10. Baltrus DA (2013) Exploring the costs of horizontal gene transfer. Trends Ecol Evol 28:489–495. doi: 10.1016/j.tree.2013.04.002 PubMedCrossRefGoogle Scholar
  11. Baltz RH (2008) Renaissance in antibacterial discovery from actinomycetes. Curr Opin Pharmacol 8:557–563. doi: 10.1016/j.coph.2008.04.008 PubMedCrossRefGoogle Scholar
  12. Basarab GS, Manchester JI, Bist S et al (2013) Fragment-to-hit-to-lead discovery of a novel pyridylurea scaffold of ATP competitive dual targeting type II topoisomerase inhibiting antibacterial agents. J Med Chem 56:8712–8735. doi: 10.1021/jm401208b PubMedCrossRefGoogle Scholar
  13. Basarab GS, Kern GH, McNulty J et al (2015) Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases. Sci Rep 5:11827. doi: 10.1038/srep11827 PubMedPubMedCentralCrossRefGoogle Scholar
  14. Bates AD, Maxwell A (2007) Energy coupling type II topoisomerase why do they hydrolyze ATP? Biochemistry 46:7929–7941. doi: 10.1021/bi700789g PubMedCrossRefGoogle Scholar
  15. Bauer A, Brönstrup M (2014) Industrial natural product chemistry for drug discovery and development. Nat Prod Rep 31:35–60. doi: 10.1039/c3np70058e PubMedCrossRefGoogle Scholar
  16. Bauer R, Dicks LMT (2005) Mode of action of lipid II-targeting lantibiotics. Int J Food Microbiol 101:201–216. doi: 10.1016/j.ijfoodmicro.2004.11.007 PubMedCrossRefGoogle Scholar
  17. Baumann S, Herrmann J, Raju R et al (2014) Cystobactamids: myxobacterial topoisomerase inhibitors exhibiting potent antibacterial activity. Angew Chem Int Ed 53:14605–14609. doi: 10.1002/anie.201409964 CrossRefGoogle Scholar
  18. Bax BD, Chan PF, Eggleston DS et al (2010) Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature 466:935–940. doi: 10.1038/nature09197 PubMedCrossRefGoogle Scholar
  19. Bénazet et al (1966) Antibiotics—advances in research, production and clinical use. In: Herold M, Gabriel Z (eds) Proceedings of the congress on antibiotics held in Prague, 15–19 June, 1964. Butterworths, London, pp 262–264Google Scholar
  20. Bengtsson B, Greko C (2014) Antibiotic resistance–consequences for animal health, welfare, and food production. Ups J Med Sci 119:96–102. doi: 10.3109/03009734.2014.901445 PubMedPubMedCentralCrossRefGoogle Scholar
  21. Bérdy J (2012) Thoughts and facts about antibiotics: where we are now and where we are heading. J Antibiot 65:441. doi: 10.1038/ja.2012.54 PubMedCrossRefGoogle Scholar
  22. Berleman J, Auer M (2013) The role of bacterial outer membrane vesicles for intra- and interspecies delivery. Environ Microbiol 15:347–354. doi: 10.1111/1462-2920.12048 PubMedCrossRefGoogle Scholar
  23. Bierbaum G, Sahl HG (1985) Induction of autolysis of staphylococci by the basic peptide antibiotics Pep 5 and nisin and their influence on the activity of autolytic enzymes. Arch Microbiol 141:249–254. doi: 10.1007/BF00408067 PubMedCrossRefGoogle Scholar
  24. Birch RG, Patil SS (1987a) Correlation between albicidin production and chlorosis induction by Xanthomonas albilineans, the sugarcane leaf scald pathogen. Physiol Mol Plant Pathol 30:199–206. doi: 10.1016/0885-5765(87)90033-6 CrossRefGoogle Scholar
  25. Birch RG, Patil SS (1987b) Evidence that an albicidin-like phytotoxin induces chlorosis in sugarcane leaf scald disease by blocking plastid DNA replication. Physiol Mol Plant Pathol 30:207–214. doi: 10.1016/0885-5765(87)90034-8 CrossRefGoogle Scholar
  26. Biswas S, Brunel J-M, Dubus J-C et al (2012) Colistin: an update on the antibiotic of the 21st century. Expert Rev Anti Infect Ther 10:917–934. doi: 10.1586/eri.12.78 PubMedCrossRefGoogle Scholar
  27. Blair JMA, Richmond GE, Piddock LJV (2014) Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. Future Microbiol 9:1165–1177. doi: 10.2217/fmb.14.66 PubMedCrossRefGoogle Scholar
  28. Bloom LB (2009) Loaing clamps for DNA replication and repair. DNA Repair 8:570–578. doi: 10.1016/j.dnarep.2008.12.014.Loading PubMedPubMedCentralCrossRefGoogle Scholar
  29. Blunt JW, Copp BR, Munro MHG et al (2011) Marine natural products. Nat Prod Rep 28:196–268. doi: 10.1039/c005001f PubMedCrossRefGoogle Scholar
  30. Boneca IG, Chiosis G (2003) Vancomycin resistance: occurrence, mechanisms and strategies to combat it. Expert Opin Ther Targets 7:311–328. doi: 10.1517/14728222.7.3.311 PubMedCrossRefGoogle Scholar
  31. Bouchaudon J (1964) Nouveau cyclopeptide, sa préparation et les médicaments qui le contiennentGoogle Scholar
  32. Boucher HW, Talbot GH, Bradley JS et al (2009) Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 48:1–12. doi: 10.1086/595011 PubMedCrossRefGoogle Scholar
  33. Boucher HW, Talbot GH, Benjamin DK et al (2013) 10 x ′20 Progress–development of new drugs active against gram-negative bacilli: an update from the Infectious diseases society of America. Clin Infect Dis 56:1685–1694. doi: 10.1093/cid/cit152 PubMedPubMedCentralCrossRefGoogle Scholar
  34. Bozdogan B, Appelbaum PC (2004) Oxazolidinones: activity, mode of action, and mechanism of resistance. Int J Antimicrob Agents 23:113–119. doi: 10.1016/j.ijantimicag.2003.11.003 PubMedCrossRefGoogle Scholar
  35. Breu F, Guggenbichler S, Wollmann J (2001) Human as the world’s greatest evolutionary force. Science 293:1786–1790CrossRefGoogle Scholar
  36. Breukink E, de Kruijff B (2006) Lipid II as a target for antibiotics. Nat Rev Drug Discov 5:321–332. doi: 10.1038/nrd2004 PubMedCrossRefGoogle Scholar
  37. Brötz H, Josten M, Wiedemann I et al (1998) Role of lipid-bound peptidoglycan precursors in the formation of pores by nisin, epidermin and other lantibiotics. Mol Microbiol 30:317–327. doi: 10.1046/j.1365-2958.1998.01065.x PubMedCrossRefGoogle Scholar
  38. Brötz-Oesterhelt H, Brunner NA (2008) How many modes of action should an antibiotic have? Curr Opin Pharmacol 8:564–573. doi: 10.1016/j.coph.2008.06.008 PubMedCrossRefGoogle Scholar
  39. Brown S, Xia G, Luhachack LG et al (2012) Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids. Proc Natl Acad Sci USA 109:18909–18914. doi: 10.1073/pnas.1209126109 PubMedPubMedCentralCrossRefGoogle Scholar
  40. Brown S, Santa Maria JP, Walker S (2013) Wall teichoic acids of gram-positive bacteria. Annu Rev Microbiol 67:313–336. doi: 10.1146/annurev-micro-092412-155620 PubMedCrossRefGoogle Scholar
  41. Brown DG, Lister T, May-Dracka TL (2014) New natural products as new leads for antibacterial drug discovery. Bioorg Med Chem Lett 24:413–418. doi: 10.1016/j.bmcl.2013.12.059 PubMedCrossRefGoogle Scholar
  42. Brown L, Wolf JM, Prados-Rosales R, Casadevall A (2015) Through the wall: extracellular vesicles in Gram-positive bacteria, mycobacteria and fungi. Nat Rev Microbiol 13:620–630. doi: 10.1038/nrmicro3480 PubMedPubMedCentralCrossRefGoogle Scholar
  43. Bunting KA, Roe SM, Pearl LH (2003) Structural basis for recruitment of translesion DNA polymerase Pol IV/DinB to the β-clamp. EMBO J 22:5883–5892. doi: 10.1093/emboj/cdg568 PubMedPubMedCentralCrossRefGoogle Scholar
  44. Burnouf DY, Olieric V, Wagner J et al (2004) Structural and biochemical analysis of sliding clamp/ligand interactions suggest a competition between replicative and translesion DNA polymerases. J Mol Biol 335:1187–1197. doi: 10.1016/j.jmb.2003.11.049 PubMedCrossRefGoogle Scholar
  45. Bush K (2010) Bench-to-bedside review: the role of beta-lactamases in antibiotic-resistant Gram-negative infections. Crit Care 14:224. doi: 10.1186/cc8892 PubMedPubMedCentralCrossRefGoogle Scholar
  46. Bush K (2015) Investigational agents for the treatment of Gram-negative bacterial infections: a reality check. ACS Infect Dis 1:509–511. doi: 10.1021/acsinfecdis.5b00100 PubMedCrossRefGoogle Scholar
  47. Butler EK, Davis RM, Bari V et al (2013a) Structure-function analysis of MurJ reveals a solvent-exposed cavity containing residues essential for peptidoglycan biogenesis in Escherichia coli. J Bacteriol 195:4639–4649. doi: 10.1128/JB.00731-13 PubMedPubMedCentralCrossRefGoogle Scholar
  48. Butler MS, Blaskovich MA, Cooper MA (2013b) Antibiotics in the clinical pipeline in 2013. J Antibiot 66:571–591. doi: 10.1038/ja.2013.86 PubMedCrossRefGoogle Scholar
  49. Butler MS, Robertson AAB, Cooper MA (2014) Natural product and natural product derived drugs in clinical trials. Nat Prod Rep 31:1612–1661. doi: 10.1039/c4np00064a PubMedCrossRefGoogle Scholar
  50. Campbell J, Singh AK, Swoboda JG et al (2012) An antibiotic that inhibits a late step in wall teichoic acid biosynthesis induces the cell wall stress stimulon in Staphylococcus aureus. Antimicrob Agents Chemother 56:1810–1820. doi: 10.1128/AAC.05938-11 PubMedPubMedCentralCrossRefGoogle Scholar
  51. Carattoli A (2013) Plasmids and the spread of resistance. Int J Med Microbiol 303:298–304. doi: 10.1016/j.ijmm.2013.02.001 PubMedCrossRefGoogle Scholar
  52. Casacuberta E, Gonzalez J (2013) The impact of transposable elements in environmental adaptation. Mol Ecol 22:1503–1517. doi: 10.1111/mec.12170 PubMedCrossRefGoogle Scholar
  53. Cervellati R, Greco E (2016) In vitro antioxidant activity of ubiquinone and ubiquinol, compared to vitamin E. Helv Chim Acta 99:41–45. doi: 10.1002/hlca.201500124 CrossRefGoogle Scholar
  54. Champoux JJ (2001) DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem 70:369–413. doi: 10.1161/01.RES.0000255691.76142.4a PubMedCrossRefGoogle Scholar
  55. Chan WC, Bycroft BW, Lian L-Y, Roberts GCK (1989) Isolation and characterisation of two degradation products derived from the peptide antibiotic nisin. FEBS Lett 252:29–36. doi: 10.1016/0014-5793(89)80884-1 CrossRefGoogle Scholar
  56. Chen Q, Duan F, Li X et al (2014) Haloemodin as novel antibacterial agent inhibiting DNA gyrase and bacterial topoisomerase i. J Med Chem 57:3707–3714. doi: 10.1021/jm401685f PubMedCrossRefGoogle Scholar
  57. Cho WK, Jergic S, Kim D et al (2014) Loading dynamics of a sliding DNA clamp. Angew Chem Int Ed 53:6768–6771. doi: 10.1002/anie.201403063 CrossRefGoogle Scholar
  58. Chopra I, Roberts M (2001) Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 65:232–260. doi: 10.1128/MMBR.65.2.232 PubMedPubMedCentralCrossRefGoogle Scholar
  59. Chopra S, Matsuyama K, Tran T et al (2012) Evaluation of gyrase B as a drug target in Mycobacterium tuberculosis. J Antimicrob Chemother 67:415–421. doi: 10.1093/jac/dkr449 PubMedCrossRefGoogle Scholar
  60. Chung BC, Zhao J, Gillespie RA et al (2013) Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. Science 341:1012–1016. doi: 10.1126/science.1236501 PubMedPubMedCentralCrossRefGoogle Scholar
  61. Clardy J, Fischbach MA, Walsh CT (2006) New antibiotics from bacterial natural products. Nat Biotechnol 24:1541–1550. doi: 10.1038/nbt1266 PubMedCrossRefGoogle Scholar
  62. Cleveland J, Montville TJ, Nes IF, Chikindas ML (2001) Bacteriocins: Safe, natural antimicrobials for food preservation. Int J Food Microbiol 71:1–20. doi: 10.1016/S0168-1605(01)00560-8 PubMedCrossRefGoogle Scholar
  63. Coates AR, Halls G, Hu Y (2011) Novel classes of antibiotics or more of the same? Br J Pharmacol 163:184–194. doi: 10.1111/j.1476-5381.2011.01250.x PubMedPubMedCentralCrossRefGoogle Scholar
  64. Cociancich S, Pesic A, Petras D et al (2015) The gyrase inhibitor albicidin consists of p-aminobenzoic acids and cyanoalanine. Nat Chem Biol 11:195–197. doi: 10.1038/nchembio.1734 PubMedCrossRefGoogle Scholar
  65. Cohen GN (2011) Microbial biochemistry, 2nd edn. Springer, HeidelbergGoogle Scholar
  66. Cole ST, Riccardi G (2011) New tuberculosis drugs on the horizon. Curr Opin Microbiol 14:570–576. doi: 10.1016/j.mib.2011.07.022 PubMedCrossRefGoogle Scholar
  67. Collin F, Karkare S, Maxwell A (2011) Exploiting bacterial DNA gyrase as a drug target: Current state and perspectives. Appl Microbiol Biotechnol 92:479–497. doi: 10.1007/s00253-011-3557-z PubMedPubMedCentralCrossRefGoogle Scholar
  68. Connor EE (1998) Sulfonamide antibiotics. Prim Care Update Ob Gyns 5:32–35CrossRefGoogle Scholar
  69. Costenaro L, Grossmann JG, Ebel C, Maxwell A (2007) Modular structure of the full-length DNA gyrase B subunit revealed by small-angle X-ray scattering. Structure 15:329–339. doi: 10.1016/j.str.2007.01.013 PubMedCrossRefGoogle Scholar
  70. Cragg GM, Newman DJ (2013) Natural products: a continuing source of novel drug leads. Biochim Biophys Acta-Gen Subj 1830:3670–3695. doi: 10.1016/j.bbagen.2013.02.008 CrossRefGoogle Scholar
  71. Czaplewski L, Bax R, Clokie M et al (2016) Alternatives to antibiotics-a pipeline portfolio review. Lancet Infect Dis 16:239–251. doi: 10.1016/S1473-3099(15)00466-1 PubMedCrossRefGoogle Scholar
  72. D’Costa VM, King CE, Kalan L et al (2011) Antibiotic resistance is ancient. Nature 477:457–461. doi: 10.1038/nature10388 PubMedCrossRefGoogle Scholar
  73. D’Elia MA, Millar KE, Beveridge TJ, Brown ED (2006a) Wall teichoic acid polymers are dispensable for cell viability in Bacillus subtilis. J Bacteriol 188:8313–8316. doi: 10.1128/JB.01336-06 PubMedPubMedCentralCrossRefGoogle Scholar
  74. D’Elia MA, Pereira MP, Chung YS et al (2006b) Lesions in teichoic acid biosynthesis in Staphylococcus aureus lead to a lethal gain of function in the otherwise dispensable pathway. J Bacteriol 188:4183–4189. doi: 10.1128/JB.00197-06 PubMedPubMedCentralCrossRefGoogle Scholar
  75. D’Elia MA, Henderson JA, Beveridge TJ et al (2009a) The N-acetylmannosamine transferase catalyzes the first committed step of teichoic acid assembly in Bacillus subtilis and Staphylococcus aureus. J Bacteriol 191:4030–4034. doi: 10.1128/JB.00611-08 PubMedPubMedCentralCrossRefGoogle Scholar
  76. D’Elia MA, Pereira MP, Brown ED (2009b) Are essential genes really essential? Trends Microbiol 17:433–438. doi: 10.1016/j.tim.2009.08.005 PubMedCrossRefGoogle Scholar
  77. Dalrymple BP, Kongsuwan K, Wijffels G et al (2001) A universal protein-protein interaction motif in the eubacterial DNA replication and repair systems. Proc Natl Acad Sci U S A 98:11627–11632. doi: 10.1073/pnas.191384398 PubMedPubMedCentralCrossRefGoogle Scholar
  78. Davies J (2006) Where have all the antibiotics gone? Can J Infect Dis Med Microbiol 17:287–290PubMedPubMedCentralGoogle Scholar
  79. Davis BD (1987) Mechanism of bactericidal action of aminoglycosides. Microbiol Rev 51:341–350 doi:0146-0749/87/030341-10$02.00/0PubMedPubMedCentralGoogle Scholar
  80. de Kruijff B, van Dam V, Breukink E (2008) Lipid II: a central component in bacterial cell wall synthesis and a target for antibiotics. Prostaglandins Leukot Essent Fat Acids 79:117–121. doi: 10.1016/j.plefa.2008.09.020 CrossRefGoogle Scholar
  81. Debnath J, Siricilla S, Wan B et al (2012) Discovery of selective menaquinone biosynthesis inhibitors against Mycobacterium tuberculosis. J Med Chem 55:3739–3755. doi: 10.1021/jm201608g PubMedPubMedCentralCrossRefGoogle Scholar
  82. Dhiman RK, Mahapatra S, Slayden RA et al (2009) Menaquinone synthesis is critical for maintaining mycobacterial viability during exponential growth and recovery from non-replicating persistence. Mol Microbiol 72:85–97. doi: 10.1111/j.1365-2958.2009.06625.x PubMedPubMedCentralCrossRefGoogle Scholar
  83. Diez J, Martinez JP, Mestres J et al (2012) Myxobacteria: natural pharmaceutical factories. Microb Cell Fact 11:52–54. doi: 10.1186/1475-2859-11-52 PubMedPubMedCentralCrossRefGoogle Scholar
  84. Donnell MO, Langston L, Stillman B et al (2013) Principles and concepts of DNA replication in bacteria, archea, and eukarya. Cold Spring Harb Perspect Biol 5:a010180. doi: 10.1101/cshperspect.a010108 CrossRefGoogle Scholar
  85. Doroghazi JR, Albright JC, Goering AW et al (2014) A roadmap for natural product discovery based on large-scale genomics and metabolomics. Nat Chem Biol 10:963–968. doi: 10.1038/nchembio.1659 PubMedPubMedCentralCrossRefGoogle Scholar
  86. Dougherty TJ, Nayar A, Newman JV et al (2014) NBTI 5463 is a novel bacterial type II topoisomerase inhibitor with Gram-negative antibacterial activity and in vivo efficacy. Antimicrob Agents Chemother. doi: 10.1128/aac.02778-13 Google Scholar
  87. Dubée V, Chau F, Arthur M et al (2011) The in vitro contribution of autolysins to bacterial killing elicited by amoxicillin increases with inoculum size in Enterococcus faecalis. Antimicrob Agents Chemother 55:910–912. doi: 10.1128/AAC.01230-10 PubMedCrossRefGoogle Scholar
  88. Edwards DI (1993) Nitroimidazole drugs–action and resistance mechanisms. I. Mechanisms of action. J Antimicrob Chemother 31:9–20. doi: 10.1093/jac/31.1.9 PubMedCrossRefGoogle Scholar
  89. Ehmann DE, Lahiri SD (2014) Novel compounds targeting bacterial DNA topoisomerase/DNA gyrase. Curr Opin Pharmacol 18:76–83. doi: 10.1016/j.coph.2014.09.007 PubMedCrossRefGoogle Scholar
  90. Eichberg MJ (2015) Public funding of clinical-stage antibiotic development in the United States and European Union. Heal Secur 13:156–165. doi: 10.1089/hs.2014.0081 CrossRefGoogle Scholar
  91. Elshahawi SI, Shaaban KA, Kharel MK, Thorson JS (2015) A comprehensive review of glycosylated bacterial natural products. Chem Soc Rev 44:7591–7697. doi: 10.1039/C4CS00426D PubMedPubMedCentralCrossRefGoogle Scholar
  92. Epand RM, Walker C, Epand RF, Magarvey NA (2016) Molecular mechanisms of membrane targeting antibiotics. BBA Biomembranes 1858:980–987. doi: 10.1016/j.bbamem.2015.10.018 PubMedCrossRefGoogle Scholar
  93. European Centre for Disease Prevention and Control (2012) Annual report of the European antimicrobial resistance surveilance network (EARS-Net). ECDC, StockholmGoogle Scholar
  94. Farha MA, Leung A, Sewell EW et al (2013) Inhibition of WTA synthesis blocks the cooperative action of pbps and sensitizes MRSA to β-lactams. ACS Chem Biol 8:226–233. doi: 10.1021/cb300413m PubMedCrossRefGoogle Scholar
  95. Finn J (2013) Evaluation of WO2012177707 and WO2012097269: Vertex’s phosphate prodrugs of gyrase and topoisomerase antibacterial agents. Expert Opin Ther Pat 23:1233–1237. doi: 10.1517/13543776.2013.820707 PubMedCrossRefGoogle Scholar
  96. Fischbach MA, Walsh CT (2009) Antibiotics for emerging pathogens. Science 325:1089–1093. doi: 10.1126/science.1176667 PubMedPubMedCentralCrossRefGoogle Scholar
  97. Floss HG, Yu T-W (2005) Rifamycin-mode of action, resistance, and biosynthesis. Chem Rev 105:621–632. doi: 10.1021/cr030112j PubMedCrossRefGoogle Scholar
  98. Forsberg KJ, Reyes A, Wang B et al (2012) The shared antibiotic resistome of soil bacteria and human pathogens. Science 337:1107–1111. doi: 10.1126/science.1220761 PubMedPubMedCentralCrossRefGoogle Scholar
  99. Frankel RB, Kalmijn AJ, Amann R et al (2006) Sampling the antibiotic resistome. Science 311:374–378. doi: 10.1126/science.1120800 CrossRefGoogle Scholar
  100. Fujimoto N, Kosaka T, Yam M (2012) Menaquinone as well as ubiquinone as a crucial component in the Escherichia coli respiratory chain. In: Ekinci D (ed) Chemical biology, pp 187–208Google Scholar
  101. Georgescu RE, Kim SS, Yurieva O et al (2008a) Structure of a sliding clamp on DNA. Cell 132:43–54. doi: 10.1016/j.cell.2007.11.045 PubMedPubMedCentralCrossRefGoogle Scholar
  102. Georgescu RE, Yurieva O, Kim S-S et al (2008b) Structure of a small-molecule inhibitor of a DNA polymerase sliding clamp. Proc Natl Acad Sci USA 105:11116–11121. doi: 10.1073/pnas.0804754105 PubMedPubMedCentralCrossRefGoogle Scholar
  103. Gerth K, Pradella S, Perlova O et al (2003) Myxobacteria: Proficient producers of novel natural products with various biological activities—past and future biotechnological aspects with the focus on the genus Sorangium. J Biotechnol 106:233–253. doi: 10.1016/j.jbiotec.2003.07.015 PubMedCrossRefGoogle Scholar
  104. Gibbons S (2004) Anti-staphylococcal plant natural products. Nat Prod Rep 21:263–277. doi: 10.1039/b212695h PubMedCrossRefGoogle Scholar
  105. Giguère S (2013) Lincosamides, pleuromutilins, and streptogramins. Antimicrob Ther Vet Med 199–210. doi: 10.1016/0007-1935(89)90107-3
  106. Gilbert GL (2015) Knowing when to stop antibiotic therapy. Med J Aust 202:121–123. doi: 10.5694/mja14.01201 PubMedCrossRefGoogle Scholar
  107. Gillings MR (2013) Evolutionary consequences of antibiotic use for the resistome, mobilome, and microbial pangenome. Front Microbiol 4:1–10. doi: 10.3389/fmicb.2013.00004 CrossRefGoogle Scholar
  108. Godtfredsen WO, Jahnsen S, Lorck H et al (1962) Fusidic acid: a new antibiotic. Nature 193:987PubMedCrossRefGoogle Scholar
  109. Górska A, Sloderbach A, Marszałł MP (2014) Siderophore-drug complexes: Potential medicinal applications of the “Trojan horse” strategy. Trends Pharmacol Sci 1–8. doi: 10.1016/j.tips.2014.06.007
  110. Gubaev A, Klostermeier D (2014) Reprint of “the mechanism of negative DNA supercoiling: a cascade of DNA-induced conformational changes prepares gyrase for strand passage”. DNA Repair (Amst) 20:130–141. doi: 10.1016/j.dnarep.2014.06.006 CrossRefGoogle Scholar
  111. Gui W-J, Lin S-Q, Chen Y-Y et al (2011) Crystal structure of DNA polymerase III β sliding clamp from Mycobacterium tuberculosis. Biochem Biophys Res Commun 405:272–277. doi: 10.1016/j.bbrc.2011.01.027 PubMedCrossRefGoogle Scholar
  112. Hamamoto H, Urai M, Ishii K et al (2014) Lysocin E is a new antibiotic that targets menaquinone in the bacterial membrane. Nat Chem Biol 11:127–133. doi: 10.1038/nchembio.1710 PubMedCrossRefGoogle Scholar
  113. Hammes WP, Neuhaus FC (1974) On the mechanism of action of vancomycin: inhibition of peptidoglycan synthesis in Gaffkya homari. Antimicrob Agents Chemother 6:722–728. doi: 10.1128/AAC.6.6.722 PubMedPubMedCentralCrossRefGoogle Scholar
  114. Harrison E, Brockhurst MA (2012) Plasmid-mediated horizontal gene transfer is a coevolutionary process. Trends Microbiol 20:262–267. doi: 10.1016/j.tim.2012.04.003 PubMedCrossRefGoogle Scholar
  115. Harvey AL, Edrada-Ebel R, Quinn RJ (2015) The re-emergence of natural products for drug discovery in the genomics era. Nat Rev Drug Discov 14:111–129. doi: 10.1038/nrd4510 PubMedCrossRefGoogle Scholar
  116. Hashimi SM, Wall MK, Smith AB et al (2007) The phytotoxin albicidin is a novel inhibitor of DNA gyrase. Antimicrob Agents Chemother 51:181–187. doi: 10.1128/AAC.00918-06 PubMedCrossRefGoogle Scholar
  117. Hawkey PM, Livermore DM (2012) Carbapenem antibiotics for serious infections. BMJ 344:1–7. doi: 10.1136/bmj.e3236 CrossRefGoogle Scholar
  118. Hawser S, Lociuro S, Islam K (2006) Dihydrofolate reductase inhibitors as antibacterial agents. Biochem Pharmacol 71:941–948. doi: 10.1016/j.bcp.2005.10.052 PubMedCrossRefGoogle Scholar
  119. Hecker SJ, Reddy KR, Totrov M et al (2015) Discovery of a cyclic boronic acid β-lactamase inhibitor (RPX7009) with utility vs class A serine carbapenemases. J Med Chem 58:3682–3692. doi: 10.1021/acs.jmedchem.5b00127 PubMedCrossRefGoogle Scholar
  120. Heide L (2014) New aminocoumarin antibiotics as gyrase inhibitors. Int J Med Microbiol 304:31–36. doi: 10.1016/j.ijmm.2013.08.013 PubMedCrossRefGoogle Scholar
  121. Henry RJ (1943) The mode of action of sulfonamides. Bacteriol Rev 7:175–262. doi: 10.1128/AEM.02766-10 PubMedPubMedCentralGoogle Scholar
  122. Herrmann J, Lukežič T, Kling A, et al (2016) Strategies for the discovery and development of new antibiotics from natural products: three case studies. Curr Top Microbiol ImmunolGoogle Scholar
  123. Hesterkamp T (2016) Antibiotics clinical development and pipeline. Curr Top Microbiol Immunol. doi: 10.1007/82_2015_451 Google Scholar
  124. Hiratsuka T, Furihata K, Ishikawa J et al (2008) An alternative menaquinone biosynthetic pathway operating in microorganisms. Science 321:1670–1673. doi: 10.1126/science.1160446 PubMedCrossRefGoogle Scholar
  125. Hirsch EB, Ledesma KR, Chang KT et al (2012) In vitro activity of MK-7655, a novel beta-lactamase inhibitor, in combination with imipenem against carbapenem-resistant Gram-negative bacteria. Antimicrob Agents Chemother 56:3753–3757. doi: 10.1128/AAC.05927-11 PubMedPubMedCentralCrossRefGoogle Scholar
  126. Holzgrabe U (2015) New griselimycins for treatment of tuberculosis. Chem Biol 22:981–982. doi: 10.1016/j.chembiol.2015.08.002 PubMedCrossRefGoogle Scholar
  127. Hooper DC, Wolfson JS, McHugh GL et al (1982) Effects of novobiocin, coumermycin-a1, clorobiocin, and their analogs on Escherichia-coli Dna gyrase and bacterial-growth. Antimicrob Agents Chemother 22:662–671PubMedPubMedCentralCrossRefGoogle Scholar
  128. Hsu S-TD, Breukink E, Tischenko E et al (2004) The nisin-lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics. Nat Struct Mol Biol 11:963–967. doi: 10.1038/nsmb830 PubMedCrossRefGoogle Scholar
  129. Huang G, Zhang L, Birch RG (2001) A multifunctional polyketide-peptide synthetase essential for albicidin biosynthesis in Xanthomonas albilineans. Microbiology 147:631–642PubMedCrossRefGoogle Scholar
  130. Jacobsson S, Golparian D, Alm RA et al (2014) High in vitro activity of the novel spiropyrimidinetrione AZD0914, a DNA gyrase inhibitor, against multidrug-resistant Neisseria gonorrhoeae isolates suggests a new effective option for oral treatment of gonorrhea. Antimicrob Agents Chemother 58:5585–5588. doi: 10.1128/AAC.03090-14 PubMedPubMedCentralCrossRefGoogle Scholar
  131. Jacoby GA (2005) Mechanisms of bacterial resistance to quinolones. 41:S120–S126Google Scholar
  132. Jad YE, Acosta GA, Naicker T et al (2015) Synthesis and biological evaluation of a teixobactin analogue. Org Lett 17:6182–6185. doi: 10.1021/acs.orglett.5b03176 PubMedCrossRefGoogle Scholar
  133. Ji C, Juárez-Hernández RE, Miller MJ (2012) Exploiting bacterial iron acquisition: siderophore conjugates. Future Med Chem 4:297–313. doi: 10.4155/fmc.11.191 PubMedCrossRefGoogle Scholar
  134. Jia Z, O’Mara ML, Zuegg J et al (2013) Vancomycin: ligand recognition, dimerization and super-complex formation. FEBS J 280:1294–1307. doi: 10.1111/febs.12121 PubMedCrossRefGoogle Scholar
  135. Johnston CW, Magarvey NA (2015) Natural products: untwisting the antibiotic’ome. Nat Chem Biol 11:177–178. doi: 10.1038/nchembio.1757 PubMedCrossRefGoogle Scholar
  136. Johnston CW, Skinnider MA, Dejong CA et al (2016) Assembly and clustering of natural antibiotics guides target identification. Nat Chem Biol 12:233–239. doi: 10.1038/nchembio.2018 PubMedCrossRefGoogle Scholar
  137. Johnstone TC, Nolan EM (2015) Beyond iron: non-classical biological functions of bacterial siderophores. Dalton Trans 44:6320–6339. doi: 10.1039/c4dt03559c PubMedPubMedCentralCrossRefGoogle Scholar
  138. Jolles G (1971) New cyclopeptides, GB Patent 1,252,553Google Scholar
  139. Kahne D, Leimkuhler C, Lu W, Walsh C (2005) Glycopeptide and lipoglycopeptide antibiotics. Chem Rev 105:425–448. doi: 10.1021/cr030103a PubMedCrossRefGoogle Scholar
  140. Kåhrström CT (2015) Antimicrobials: a new drug for resistant bugs. Nat Rev Microbiol 13:126–127. doi: 10.1038/nrmicro3429 PubMedCrossRefGoogle Scholar
  141. Kale MG, Raichurkar A, Shahul Hameed P et al (2013) Thiazolopyridine ureas as novel antitubercular agents acting through inhibition of DNA gyrase B. J Med Chem 56:8834–8848. doi: 10.1021/jm401268f PubMedCrossRefGoogle Scholar
  142. Kale RR, Kale MG, Waterson D et al (2014) Thiazolopyridone ureas as DNA gyrase B inhibitors: optimization of antitubercular activity and efficacy. Bioorg Med Chem Lett 24:870–879. doi: 10.1016/j.bmcl.2013.12.080 PubMedCrossRefGoogle Scholar
  143. Kalman D, Barriere S (1990) Review of the pharmacology, pharmacokinetics, and clinical use of cephalosporins. Tex Heart Inst J 17:203–215PubMedPubMedCentralGoogle Scholar
  144. Kannan K, Mankin AS (2011) Macrolide antibiotics in the ribosome exit tunnel: species-specific binding and action. Ann N Y Acad Sci 1241:33–47. doi: 10.1111/j.1749-6632.2011.06315.x PubMedCrossRefGoogle Scholar
  145. Kawamukai M (2002) Biosynthesis, Bioproduction and Novel Roles of Ubiquinone. J Biosci Bioeng 94:511–517PubMedCrossRefGoogle Scholar
  146. Keller S, Schadt HS, Ortel I, Süssmuth RD (2007) Action of atrop-abyssomicin C as an inhibitor of 4-amino-4-deoxychorismate synthase PabB. Angew Chem Int Ed 46:8284–8286. doi: 10.1002/anie.200701836 CrossRefGoogle Scholar
  147. Kern G, Palmer T, Ehmann DE, et al (2015) Inhibition of Neisseria gonorrhoeae type II Topoisomerases by the Novel Spiropyrimidinetrione AZD0914. J Biol Chem M115.663534. doi: 10.1074/jbc.M115.663534
  148. Kirst HA (2013) Developing new antibacterials through natural product research. Expert Opin Drug Discov 8:479–493. doi: 10.1517/17460441.2013.779666 PubMedCrossRefGoogle Scholar
  149. Kjelstrup S, Hansen PMP, Thomsen LE et al (2013) Cyclic Peptide Inhibitors of the β-Sliding Clamp in Staphylococcus aureus. PLoS ONE. doi: 10.1371/journal.pone.0072273 PubMedPubMedCentralGoogle Scholar
  150. Kling A, Lukat P, Almeida DV et al (2015) Targeting DnaN for tuberculosis therapy using novel griselimycins. Science 348:1106–1112. doi: 10.1126/science.aaa4690 PubMedCrossRefGoogle Scholar
  151. Koehn FE, Carter GT (2005) The evolving role of natural products in drug discovery. Nat Rev Drug Discov 4:206–220. doi: 10.1038/nrd1657 PubMedCrossRefGoogle Scholar
  152. Kohanski MA, Dwyer DJ, Collins JJ (2010) How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol 8:423–435. doi: 10.1038/nrmicro2333 PubMedPubMedCentralCrossRefGoogle Scholar
  153. Kotra LP, Haddad J, Mobashery S (2000) Aminoglycosides: perspectives on mechanisms of action and resistance and strategies to counter resistance. Antimicrob Agents Chemother 44:3249–3256. doi: 10.1128/AAC.44.12.3249-3256.2000.Updated PubMedPubMedCentralCrossRefGoogle Scholar
  154. Kramer NE, Smid EJ, Kok J et al (2004) Resistance of Gram-positive bacteria to nisin is not determined by Lipid II levels. FEMS Microbiol Lett 239:157–161. doi: 10.1016/j.femsle.2004.08.033 PubMedCrossRefGoogle Scholar
  155. Kretz J, Kerwat D, Schubert V et al (2015) Total synthesis of albicidin: A lead structure from xanthomonas albilineans for potent antibacterial gyrase inhibitors. Angew Chem Int Ed 54:1969–1973. doi: 10.1002/anie.201409584 CrossRefGoogle Scholar
  156. Kuipers OP, Rollema HS, de Vos WM, Siezen RJ (1993) Biosynthesis and secretion of a precursor of nisin Z by Lactococcus lactis, directed by the leader peptide of the homologous lantibiotic subtilin from Bacillus subtilis. FEBS Lett 330:23–27. doi: 10.1016/0014-5793(93)80911-D PubMedCrossRefGoogle Scholar
  157. Kurosu M, Begari E (2010) Vitamin K2 in electron transport system: are enzymes involved in vitamin K2 biosynthesis promising drug targets? Molecules 15:1531–1553. doi: 10.3390/molecules15031531 PubMedCrossRefGoogle Scholar
  158. Kurosu M, Narayanasamy P, Biswas K et al (2007) Discovery of 1,4-didydroxy-2-naphthoate prenyltransferase inhibitors: new drug leads for multidrug-resistant gram-positive pathogens. J Med Chem 50:3973–3975. doi: 10.1021/jm070638m PubMedPubMedCentralCrossRefGoogle Scholar
  159. Lapierre P, Gogarten JP (2009) Estimating the size of the bacterial pan-genome. Trends Genet 25:107–110. doi: 10.1016/j.tig.2008.12.004 PubMedCrossRefGoogle Scholar
  160. Lapuebla A, Abdallah M, Olafisoye O et al (2015a) Activity of imipenem with relebactam against gram-negative pathogens from New York City: Table 1. Antimicrob Agents Chemother 59:5029–5031. doi: 10.1128/AAC.00830-15 PubMedPubMedCentralCrossRefGoogle Scholar
  161. Lapuebla A, Abdallah M, Olafisoye O, et al (2015b) Activity of meropenem combined with RPX7009, a novel β-lactamase inhibitor, against Gram-negative clinical isolates in New York City. Antimicrob Agents Chemother 59:AAC.00843–15. doi: 10.1128/AAC.00843-15
  162. Lazarevic V, Karamata D (1995) The tagGH operon of Bacillus subtilis 168 encodes a two-component ABC transporter involved in the metabolism of two wall teichoic acids. Mol Microbiol 16:345–355. doi: 10.1111/j.1365-2958.1995.tb02306.x PubMedCrossRefGoogle Scholar
  163. Lee K, Campbell J, Swoboda JG et al (2010) Development of improved inhibitors of wall teichoic acid biosynthesis with potent activity against Staphylococcus aureus. Bioorg Med Chem Lett 20:1767–1770. doi: 10.1016/j.bmcl.2010.01.036 PubMedPubMedCentralCrossRefGoogle Scholar
  164. Lee SH, Wang H, Labroli M, et al (2016a) TarO-specific inhibitors of wall teichoic acid biosynthesis restore b -lactam efficacy against methicillin-resistant staphylococci. Sci Transl Med 8:329ra32. doi: 10.1126/scitranslmed.aad7364
  165. Lee W, Schaefer K, Qiao Y et al (2016b) The mechanism of action of lysobactin. J Am Chem Soc 138:100–103. doi: 10.1021/jacs.5b11807 PubMedCrossRefGoogle Scholar
  166. Leski TA, Tomasz A (2005) Role of penicillin-binding protein 2 (PBP2) in the antibiotic susceptibility and cell wall cross-linking of Staphylococcus aureus. J Bacteriol 2:1815–1824. doi: 10.1128/JB.187.5.1815 CrossRefGoogle Scholar
  167. Leu FP, Hingorani MM, Turner J, O’Donnell M (2000) The δ subunit of DNA polymerase III holoenzyme serves as a sliding clamp unloader in Escherichia coli. J Biol Chem 275:34609–34618. doi: 10.1074/jbc.M005495200 PubMedCrossRefGoogle Scholar
  168. Lewis K (2013) Platforms for antibiotic discovery. Nat Rev Drug Discov 12:371–387. doi: 10.1038/nrd3975 PubMedCrossRefGoogle Scholar
  169. Lim D, Strynadka NCJ (2002) Structural basis for the beta lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nat Struct Biol 9:870–876. doi: 10.1038/nsb858 PubMedGoogle Scholar
  170. Lin AH, Murray RW, Vidmar TJ, Marotti KR (1997) The oxazolidinone eperezolid binds to the 50S ribosomal subunit and competes with binding of chloramphenicol and lincomycin. Antimicrob Agents Chemother 41:2127–2131PubMedPubMedCentralGoogle Scholar
  171. Ling LL, Schneider T, Peoples AJ et al (2015) A new antibiotic kills pathogens without detectable resistance. Nature 517:455–459. doi: 10.1038/nature14098 CrossRefGoogle Scholar
  172. Lipsky BA, Baker CA (1999) Fluoroquinolone toxicity profiles: a review focusing on newer agents. Clin Infect Dis 28:352–364. doi: 10.1086/515104 PubMedCrossRefGoogle Scholar
  173. Littmann J, Buyx A, Cars O (2015) Antibiotic resistance: An ethical challenge. Int J Antimicrob Agents 46:359–361. doi: 10.1016/j.ijantimicag.2015.06.010 PubMedCrossRefGoogle Scholar
  174. Liu LF, Liu CC, Alberts BM (1980) Type II DNA topoisomerases: enzymes that can unknot a topologically knotted DNA molecule via a reversible double-strand break. Cell 19:697–707. doi: 10.1016/S0092-8674(80)80046-8 PubMedCrossRefGoogle Scholar
  175. Livermore DM, Warner M, Mushtaq S (2013) Activity of MK-7655 combined with imipenem against enterobacteriaceae and Pseudomonas aeruginosa. J Antimicrob Chemother 68:2286–2290. doi: 10.1093/jac/dkt178 PubMedGoogle Scholar
  176. Livermore DM, Mushtaq S, Warner M, Woodford N (2015) Activity of OP0595/β-lactam combinations against Gram-negative bacteria with extended-spectrum, AmpC and carbapenem-hydrolysing β-lactamases. J Antimicrob Chemother 70:3032–3041. doi: 10.1093/jac/dkv239 PubMedCrossRefGoogle Scholar
  177. Lowther GE (1979) The united states food and drug administration and the practice of optometry. J Am Optom Assoc 50:579–582PubMedGoogle Scholar
  178. Lu X, Zhou R, Sharma I et al (2012) Stable analogues of OSB-AMP: potent Inhibitors of MenE, the o-succinylbenzoate-CoA synthetase from bacterial menaquinone biosynthesis. ChemBioChem 13:129–136. doi: 10.1002/cbic.201100585 PubMedCrossRefGoogle Scholar
  179. Maki H, Yamaguchi T, Murakami K (1994) Cloning and characterization of a gene affecting the methicillin resistance level and the autolysis rate in Staphylococcus aureus. J Bacteriol 176:4993–5000PubMedPubMedCentralCrossRefGoogle Scholar
  180. Maren TH (1976) Relatons between structure and biological activity of sulfonamides. Annu Rev Pharmacol Toxicol 16:309–327. doi: 10.1146/annurev.pa.16.040176.001521 PubMedCrossRefGoogle Scholar
  181. Martin NI, Breukink E (2007) Expanding role of lipid II as a target for lantibiotics. Future Microbiol 2:513–525. doi: 10.2217/17460913.2.5.513 PubMedCrossRefGoogle Scholar
  182. Mast Y, Wohlleben W (2014) International Journal of Medical Microbiology Streptogramins – Two are better than one ! 304:44–50Google Scholar
  183. Maxwell A (1993) The interaction between coumarin drugs and DNA gyrase. Mol Microbiol 9:681–686. doi: 10.1111/j.1365-2958.1993.tb01728.x PubMedCrossRefGoogle Scholar
  184. Maxwell A, Lawson DM (2003) The ATP-binding site of type II topoisomerases as a target for antibacterial drugs. Curr Top Med Chem 3:283–303. doi: 10.2174/1568026033452500 PubMedCrossRefGoogle Scholar
  185. Mayer C, Janin YL (2014) Non-quinolone inhibitors of bacterial type IIA topoisomerases: a feat of bioisosterism. Chem Rev 114:2313–2342PubMedCrossRefGoogle Scholar
  186. Mccomas CC, Mccomas CC, Crowley BM et al (2003) Partitioning the loss in vancomycin binding affinity for D-Ala-D-Lac into lost H-bond and repulsive lone pair contributions. J Am Chem Soc 125:9314–9315PubMedCrossRefGoogle Scholar
  187. Medini D, Donati C, Tettelin H et al (2005) The microbial pan-genome. Curr Opin Genet Dev 15:589–594. doi: 10.1016/j.gde.2005.09.006 PubMedCrossRefGoogle Scholar
  188. Meeske AJ, Sham L-T, Kimsey H et al (2015) MurJ and a novel lipid II flippase are required for cell wall biogenesis in Bacillus subtilis. Proc Natl Acad Sci U S A 112:6437–6442. doi: 10.1073/pnas.1504967112 PubMedPubMedCentralCrossRefGoogle Scholar
  189. Meredith TC, Swoboda JG, Walker S (2008) Late-stage polyribitol phosphate wall teichoic acid biosynthesis in Staphylococcus aureus. J Bacteriol 190:3046–3056. doi: 10.1128/JB.01880-07 PubMedPubMedCentralCrossRefGoogle Scholar
  190. Michalopoulos AS, Livaditis IG, Gougoutas V (2011) The revival of fosfomycin. Int J Infect Dis 15:e732–e739. doi: 10.1016/j.ijid.2011.07.007 PubMedCrossRefGoogle Scholar
  191. Miles TJ, Hennessy AJ, Bax B et al (2013) Novel hydroxyl tricyclics (e.g., GSK966587) as potent inhibitors of bacterial type IIA topoisomerases. Bioorg Med Chem Lett 23:5437–5441. doi: 10.1016/j.bmcl.2013.07.013 PubMedCrossRefGoogle Scholar
  192. Miller EL (2002) The penicillins: a review and update. J Midwifery Women’s Heal 47:426–434. doi: 10.1016/S1526-9523(02)00330-6 CrossRefGoogle Scholar
  193. Mislin GL, Schalk IJ (2014) Siderophore-dependent iron uptake systems as gates for antibiotic Trojan horse strategies against Pseudomonas aeruginosa. Metallomics 6:408–420. doi: 10.1039/c3mt00359k PubMedCrossRefGoogle Scholar
  194. Mital A (2009) Synthetic nitroimidazoles: biological activities and mutagenicity relationships. Sci Pharm 77:497–520. doi: 10.3797/scipharm.0907-14 CrossRefGoogle Scholar
  195. Mizrahi V, Henrie RN, Marlier JF et al (1985) Rate-limiting steps in the DNA polymerase I reaction pathway. Biochemistry 24:4010–4018. doi: 10.1021/bi00336a031 PubMedCrossRefGoogle Scholar
  196. Mohammadi T, Karczmarek A, Crouvoisier M et al (2007) The essential peptidoglycan glycosyltransferase MurG forms a complex with proteins involved in lateral envelope growth as well as with proteins involved in cell division in Escherichia coli. Mol Microbiol 65:1106–1121. doi: 10.1111/j.1365-2958.2007.05851.x PubMedPubMedCentralCrossRefGoogle Scholar
  197. Mohammadi T, van Dam V, Sijbrandi R et al (2011) Identification of FtsW as a transporter of lipid-linked cell wall precursors across the membrane. EMBO J 30:1425–1432. doi: 10.1038/emboj.2011.61 PubMedPubMedCentralCrossRefGoogle Scholar
  198. Moreno M, Elgaher WAM, Herrmann J et al (2015) Synthesis and biological evaluation of cystobactamid 507: a bacterial topoisomerase inhibitor from Cystobacter sp. Synlett 26:1175–1178. doi: 10.1055/s-0034-1380509 CrossRefGoogle Scholar
  199. Morrison C (2015) Antibacterial antibodies gain traction. Nat Rev Drug Discov 14:737–738. doi: 10.1038/nrd4770 PubMedCrossRefGoogle Scholar
  200. Mullane KM, Gorbach S (2011) Fidaxomicin: first-in-class macrocyclic antibiotic. Expert Rev Anti Infect Ther 9:767–777. doi: 10.1586/eri.11.53 PubMedCrossRefGoogle Scholar
  201. Münch D, Roemer T, Lee SH et al (2012) Identification and in vitro analysis of the GatD/MurT enzyme-complex catalyzing lipid II amidation in Staphylococcus aureus. PLoS Pathog 8:1–11. doi: 10.1371/journal.ppat.1002509 CrossRefGoogle Scholar
  202. Münch D, Engels I, Müller A et al (2015) Structural variations of the cell wall precursor lipid II and their influence on binding and activity of the lipoglycopeptide antibiotic oritavancin. Antimicrob Agents Chemother 59:772–781. doi: 10.1128/AAC.02663-14 PubMedPubMedCentralCrossRefGoogle Scholar
  203. Murai M, Kaji T, Kuranaga T et al (2015) Total synthesis and biological evaluation of the antibiotic lysocin E and its enantiomeric, epimeric, and N-demethylated analogues. Angew Chem Int Ed 54:1556–1560. doi: 10.1002/anie.201410270 CrossRefGoogle Scholar
  204. Nesme J, Simonet P (2015) The soil resistome: a critical review on antibiotic resistance origins, ecology and dissemination potential in telluric bacteria. Environ Microbiol 17:913–930. doi: 10.1111/1462-2920.12631 PubMedCrossRefGoogle Scholar
  205. Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75:311–335. doi: 10.1021/np200906s PubMedPubMedCentralCrossRefGoogle Scholar
  206. Nichols D, Cahoon N, Trakhtenberg EM et al (2010) Use of ichip for high-throughput in situ cultivation of “uncultivable” microbial species. Appl Environ Microbiol 76:2445–2450. doi: 10.1128/AEM.01754-09 PubMedPubMedCentralCrossRefGoogle Scholar
  207. Nicolau DP (2008) Carbapenems: a potent class of antibiotics. Expert Opin Pharmacother 9:23–37. doi: 10.1517/14656566.9.1.23 PubMedCrossRefGoogle Scholar
  208. Niiranen L, Lian K, Johnson KA, Moe E (2015) Crystal structure of the DNA polymerase III β subunit (β-clamp) from the extremophile Deinococcus radiodurans. BMC Struct Biol. doi: 10.1186/s12900-015-0032-6
  209. Nikaido H (2003) Molecular basis of bacterial outer membrane permeability revisited. Microbiol Mol Biol Rev 67:593–656. doi: 10.1128/MMBR.67.4.593 PubMedPubMedCentralCrossRefGoogle Scholar
  210. Nöllmann M, Crisona NJ, Arimondo PB (2007) Thirty years of Escherichia coli DNA gyrase: From in vivo function to single-molecule mechanism. Biochimie 89:490–499. doi: 10.1016/j.biochi.2007.02.012 PubMedCrossRefGoogle Scholar
  211. Noufflard-Guy-Loé H, Berteaux S (1965) Rev Tuberc Pneumol 29:301–326Google Scholar
  212. Novak R (2011) Are pleuromutilin antibiotics finally fit for human use? Ann N Y Acad Sci 1241:71–81. doi: 10.1111/j.1749-6632.2011.06219.x PubMedCrossRefGoogle Scholar
  213. Nowicka B, Kruk J (2010) Occurrence, biosynthesis and function of isoprenoid quinones. Biochim Biophys Acta Bioenerg 1797:1587–1605. doi: 10.1016/j.bbabio.2010.06.007 CrossRefGoogle Scholar
  214. O’Connell KMG, Hodgkinson JT, Sore HF et al (2013) Combating multidrug-resistant bacteria: Current strategies for the discovery of novel antibacterials. Angew Chem Int Ed 52:10706–10733. doi: 10.1002/anie.201209979 CrossRefGoogle Scholar
  215. O’Neill J (2015) Securing new drugs for future generations : the pipeline of antibiotics. Wellcome Trust, LondonGoogle Scholar
  216. Oakley AJ, Prosselkov P, Wijffels G et al (2003) Flexibility revealed by the 1.85 Å crystal structure of the $β$ sliding-clamp subunit of Escherichia coli DNA polymerase III. Acta Crystallogr Sect D 59:1192–1199. doi: 10.1107/S0907444903009958 CrossRefGoogle Scholar
  217. Oliphant CM, Green GM (2002) Quinolones: a comprehensive review. Am Fam Physician 65:455–464PubMedGoogle Scholar
  218. Opperman TJ, Nguyen ST (2015) Recent advances toward a molecular mechanism of efflux pump inhibition. Front Microbiol 6:1–16. doi: 10.3389/fmicb.2015.00421 CrossRefGoogle Scholar
  219. Ozawa K, Horan NP, Robinson A et al (2013) Proofreading exonuclease on a tether: the complex between the E. coli DNA polymerase III subunits α, ε, θ and β reveals a highly flexible arrangement of the proofreading domain. Nucleic Acids Res 41:5354–5367. doi: 10.1093/nar/gkt162 PubMedPubMedCentralCrossRefGoogle Scholar
  220. Page MGP (2013) Siderophore conjugates. Ann N Y Acad Sci 1277:115–126. doi: 10.1111/nyas.12024 PubMedCrossRefGoogle Scholar
  221. Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA (2011) Carbapenems: past, present, and future. Antimicrob Agents Chemother 55:4943–4960. doi: 10.1128/AAC.00296-11 PubMedPubMedCentralCrossRefGoogle Scholar
  222. Paris L (2015) Report of the Antibiotics resistance project: antibiotics currently in clinical development. http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-development
  223. Parmar A, Iyer A, Vincent CS et al (2016) Efficient total syntheses and biological activities of two teixobactin analogues. Chem Commun 52:6060–6063. doi: 10.1039/C5CC10249A CrossRefGoogle Scholar
  224. Payne DJ, Gwynn MN, Holms DJ, Pompliano DL (2007) Drugs for bad bugs: confronting the challanges of antibacterial discovery. Nat Rev Drug Discov 6:29–40PubMedCrossRefGoogle Scholar
  225. Pelchovich G, Omer-Bendori S, Gophna U (2013) Menaquinone and iron are essential for complex colony development in Bacillus subtilis. PLoS ONE 8:1–14. doi: 10.1371/journal.pone.0079488 CrossRefGoogle Scholar
  226. Pendleton JN, Gorman SP, Gilmore BF (2013) Clinical relevance of the ESKAPE pathogens. Expert Rev Anti Infect Ther 11:297–308. doi: 10.1586/eri.13.12 PubMedCrossRefGoogle Scholar
  227. Pereira MP, Schertzer JW, D’Elia MA et al (2008) The wall teichoic acid polymerase TagF efficiently synthesizes poly(glycerol phosphate) on the TagB product lipid III. ChemBioChem 9:1385–1390. doi: 10.1002/cbic.200800026 PubMedCrossRefGoogle Scholar
  228. Perez-Cruz C, Delgado L, Lopez-Iglesias C, Mercade E (2015) Outer-inner membrane vesicles naturally secreted by gram-negative pathogenic bacteria. PLoS ONE 10:1–18. doi: 10.1371/journal.pone.0116896 Google Scholar
  229. Perry JA, Westman EL, Wright GD (2014) The antibiotic resistome: what’ s new? Curr Opin Microbiol 21:45–50. doi: 10.1016/j.mib.2014.09.002 PubMedCrossRefGoogle Scholar
  230. Peterson LR (2009) Bad bugs, no drugs: no ESCAPE revisited. Clin Infect Dis 49:992–993. doi: 10.1086/605540 PubMedCrossRefGoogle Scholar
  231. Piddock LJV (2012) The crisis of no new antibiotics-what is the way forward? Lancet Infect Dis 12:249–253. doi: 10.1016/S1473-3099(11)70316-4 PubMedCrossRefGoogle Scholar
  232. Piddock LJV (2015) Teixobactin, the first of a new class of antibiotics discovered by ichip technology? J Antimicrob Chemother 70:2679–2680. doi: 10.1093/jac/dkv175 PubMedCrossRefGoogle Scholar
  233. Piel J (2010) Biosynthesis of polyketides by trans-AT polyketide synthases. Nat Prod Rep 27:996–1047. doi: 10.1039/b816430b PubMedCrossRefGoogle Scholar
  234. Pinho MG, Errington J (2005) Recruitment of penicillin-binding protein PBP2 to the division site of Staphylococcus aureus is dependent on its transpeptidation substrates. Mol Microbiol 55:799–807. doi: 10.1111/j.1365-2958.2004.04420.x PubMedCrossRefGoogle Scholar
  235. Pinho MG, de Lencastre H, Tomasz A (2001) An acquired and a native penicillin-binding protein cooperate in building the cell wall of drug-resistant staphylococci. Proc Natl Acad Sci USA 98:10886–10891. doi: 10.1073/pnas.191260798 PubMedPubMedCentralCrossRefGoogle Scholar
  236. Policy IP (2010) The 10 × ‘20 initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin Infect Dis 50:1081–1083. doi: 10.1086/652237 CrossRefGoogle Scholar
  237. Polz MF, Alm EJ, Hanage WP (2013) Horizontal gene transfer and the evolution of bacterial and archaeal population structure. Trends Genet 29:170–175. doi: 10.1016/j.tig.2012.12.006 PubMedPubMedCentralCrossRefGoogle Scholar
  238. Powers JH (2003) Development of drugs for antimicrobial-resistant pathogens. Curr Opin Infect Dis 16:547–551. doi: 10.1097/01.qco.0000104294.87920.b4 PubMedCrossRefGoogle Scholar
  239. Projan SJ (2003) Why is big Pharma getting out of antibacterial drug discovery? Curr Opin Microbiol 6:427–430. doi: 10.1016/j.mib.2003.08.003 PubMedCrossRefGoogle Scholar
  240. Pucci MJ, Bush K (2013) Investigational antimicrobial agents of 2013. Clin Microbiol Rev 26:792–821. doi: 10.1128/CMR.00033-13 PubMedPubMedCentralCrossRefGoogle Scholar
  241. Rasko DA, Sperandio V (2010) Anti-virulence strategies to combat bacteria-mediated disease. Nat Rev Drug Discov 9:117–128. doi: 10.1038/nrd3013 PubMedCrossRefGoogle Scholar
  242. Rawat D, Nair D (2010) Extended-spectrum beta-lactamases in gram negative bacteria. J Glob Infect Dis 2:263–274. doi: 10.4103/0974-777X.68531 PubMedPubMedCentralCrossRefGoogle Scholar
  243. Reck F, Alm RA, Brassil P et al (2012) Novel N-linked aminopiperidine inhibitors of bacterial topoisomerase type II with reduced p K a: antibacterial agents with an improved safety profile. J Med Chem 55:6916–6933. doi: 10.1021/jm300690s PubMedCrossRefGoogle Scholar
  244. Redgrave LS, Sutton SB, Webber MA, Piddock LJV (2014) Fluoroquinolone resistance: mechanisms, impact on bacteria, and role in evolutionary success. Trends Microbiol 22:438–445. doi: 10.1016/j.tim.2014.04.007 PubMedCrossRefGoogle Scholar
  245. Rex JH (2014) ND4BB: addressing the antimicrobial resistance crisis. Nat Rev Microbiol 12:231–232. doi: 10.1038/nrmicro3245 CrossRefGoogle Scholar
  246. Robinson A, Causer RJ, Dixon NE (2012) Architecture and conservation of the bacterial DNA replication machinery, an underexploited drug target. Curr Drug Targets 13:352–372. doi: 10.2174/138945012799424598
  247. Roca J, Wang JC (1992) The capture of a DNA double helix by an ATP-dependent protein clamp: a key step in DNA transport by type II DNA topoisomerases. Cell 71:833–840. doi: 10.1016/0092-8674(92)90558-T PubMedCrossRefGoogle Scholar
  248. Roca J, Wang JC (1994) DNA transport by a type II DNA topoisomerase: evidence in favor of a two-gate mechanism. Cell 77:609–616. doi: 10.1016/0092-8674(94)90222-4 PubMedCrossRefGoogle Scholar
  249. Roca J, Berger JM, Harrison SC, Wang JC (1996) DNA transport by a type II topoisomerase: direct evidence for a two-gate mechanism. Proc Natl Acad Sci U S A 93:4057–4062. doi: 10.1073/pnas.93.9.4057 PubMedPubMedCentralCrossRefGoogle Scholar
  250. Rodríguez-Rojas A, Rodríguez-Beltrán J, Couce A, Blázquez J (2013) Antibiotics and antibiotic resistance: A bitter fight against evolution. Int J Med Microbiol 303:293–297. doi: 10.1016/j.ijmm.2013.02.004 PubMedCrossRefGoogle Scholar
  251. Royer M, Costet L, Vivien E et al (2004) Albicidin pathotoxin produced by Xanthomonas albilineans is encoded by three large PKS and NRPS genes present in a gene cluster also containing several putative modifying, regulatory, and resistance genes. Mol Plant Microbe Interact 17:414–427PubMedCrossRefGoogle Scholar
  252. Saha R, Saha N, Donofrio RS, Bestervelt LL (2013) Microbial siderophores: a mini review. J Basic Microbiol 53:303–317. doi: 10.1002/jobm.201100552 PubMedCrossRefGoogle Scholar
  253. Sanchez S, Demain AL (eds) (2015) Antibiotics: current innovations and future trends. Caister Academic Press, NorfolkGoogle Scholar
  254. Sauvage E, Kerff F, Terrak M et al (2008) The penicillin-binding proteins: Structure and role in peptidoglycan biosynthesis. FEMS Microbiol Rev 32:234–258. doi: 10.1111/j.1574-6976.2008.00105.x PubMedCrossRefGoogle Scholar
  255. Savoia D (2012) Plant-derived antimicrobial compounds: alternatives to antibiotics. Future Microbiol 7:979–990. doi: 10.2217/fmb.12.68 PubMedCrossRefGoogle Scholar
  256. Schäberle TF, Lohr F, Schmitz A, König GM (2014) Antibiotics from myxobacteria. Nat Prod Rep 31:953. doi: 10.1039/c4np00011k PubMedCrossRefGoogle Scholar
  257. Schaefer B (2014) Natural Products in the Chemical Industry. Springer, Berlin & HeidelbergGoogle Scholar
  258. Schoeffler AJ, Berger JM (2008) DNA topoisomerases: harnessing and constraining energy to govern chromosome topology. Q Rev Biophys 41:41–101. doi: 10.1017/S003358350800468X PubMedCrossRefGoogle Scholar
  259. Schoepp-Cothenet B, Lieutaud C, Baymann F et al (2009) Menaquinone as pool quinone in a purple bacterium. Proc Natl Acad Sci U S A 106:8549–8554. doi: 10.1073/pnas.0813173106 PubMedPubMedCentralCrossRefGoogle Scholar
  260. Schueffler A, Anke T (2014) Fungal natural products in research and development. Nat Prod Rep 1425–1448. doi: 10.1039/C4NP00060A
  261. Schwartz B, Markwalder JA, Wang Y (2001) Lipid II: total synthesis of the bacterial cell wall precursor and utilization as a substrate for glycosyltransfer and transpeptidation by penicillin binding protein (PBP) 1b of Eschericia coli. J Am Chem Soc 123:11638–11643. doi: 10.1021/ja0166848 PubMedCrossRefGoogle Scholar
  262. Schwechheimer C, Kuehn MJ (2015) Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions. Nat Rev Microbiol 13:605–619. doi: 10.1038/nrmicro3525 PubMedCrossRefGoogle Scholar
  263. Scott LJ (2013) Fidaxomicin: a review of its use in patients with clostridium difficile infection. Drugs 73:1733–1747. doi: 10.1007/s40265-013-0134-z PubMedCrossRefGoogle Scholar
  264. Scott CP, Abel-Santos E, Wall M et al (1999) Production of cyclic peptides and proteins in vivo. Proc Natl Acad Sci U S A 96:13638–13643. doi: 10.1073/pnas.96.24.13638 PubMedPubMedCentralCrossRefGoogle Scholar
  265. Sewell EWC, Brown ED (2014) Taking aim at wall teichoic acid synthesis: new biology and new leads for antibiotics. J Antibiot 67:43–51. doi: 10.1038/ja.2013.100 PubMedCrossRefGoogle Scholar
  266. Shahul HP, Solapure S, Mukherjee K et al (2014) Optimization of pyrrolamides as mycobacterial gyrb atpase inhibitors: structure-activity relationship and in vivo efficacy in a mouse model of tuberculosis. Antimicrob Agents Chemother 58:61–70. doi: 10.1128/AAC.01751-13 CrossRefGoogle Scholar
  267. Sham L-T, Butler EK, Lebar MD et al (2014) MurJ is the flippase of lipid-linked precursors for peptidoglycan biogenesis. Science 345:220–222PubMedPubMedCentralCrossRefGoogle Scholar
  268. Sharma M, Chauhan PM (2012) Dihydrofolate reductase as a therapeutic target for infectious diseases: opportunities and challenges. Future Med Chem 4:1335–1365. doi: 10.4155/fmc.12.68 PubMedCrossRefGoogle Scholar
  269. Shiva F (2015) Antibiotic prescription and bacterial resistance. Arch Pediatr Infect Dis 3:e21540. doi: 10.5812/pedinfect.21540 CrossRefGoogle Scholar
  270. Silver LL (2007) Multi-targeting by monotherapeutic antibacterials. Nat Rev Drug Discov 6:41–55. doi: 10.1038/nrd2202 PubMedCrossRefGoogle Scholar
  271. Singh GS (2004) β-Lactams in the new millennium. Part-I : monobactams and carbapenems. Med Chem (Los Angeles) 4:62–92Google Scholar
  272. Smillie C, Garcillan-Barcia MP, Francia MV et al (2010) Mobility of plasmids. Microbiol Mol Biol Rev 74:434–452. doi: 10.1128/MMBR.00020-10 PubMedPubMedCentralCrossRefGoogle Scholar
  273. Spellberg B, Powers JH, Brass EP et al (2004) Trends in antimicrobial drug development: implications for the future 90502:1279–1286Google Scholar
  274. Stadler M, Hoffmeister D (2015) Fungal natural products-the mushroom perspective. Front Microbiol 6:1–4. doi: 10.3389/fmicb.2015.00127 CrossRefGoogle Scholar
  275. Storm DR, Strominger JL (1974) Binding of bacitracin to cells and protoplasts of Micrococcus lysodeikticus. J Biol Chem 249:1823–1827PubMedGoogle Scholar
  276. Stukenberg PT, Studwell-Vaughan PS, O’Donnell M, O’Donnell M (1991) Mechanism of the sliding beta-clamp of DNA polymerase III holoenzyme. J Biol Chem 266:11328–11334. doi: 10.1074/jbc.M111.338145 PubMedGoogle Scholar
  277. Su X-H, Wang B-X, Le W-J et al (2016) Multidrug-resistant neisseria gonorrhoeae Isolates from Nanjing, China, are sensitive to killing by a novel DNA gyrase inhibitor, ETX0914 (AZD0914). Antimicrob Agents Chemother 60:621–623. doi: 10.1128/AAC.01211-15 CrossRefGoogle Scholar
  278. Swoboda JG, Meredith TC, Cambell J et al (2010) Discovery of a small molecule that blocks wall teichoic acid biosynthesis in Stphylococcus aureus. ACS Chem Biol 5:839–849CrossRefGoogle Scholar
  279. Swoboda JG, Mylonakis E, Wilkinson BJ, Walker S (2011) Synthetic lethal compound combinations reveal a fundamental connection between wall teichoic acid and peptidoglycan biosynthesis in Staphylococcus aureus. ACS Chem Biol 6:106–116PubMedCrossRefGoogle Scholar
  280. Syvanen M (2012) Evolutionary implications of horizontal gene transfer. Annu Rev Genet 46:341–358. doi: 10.1146/annurev-genet-110711-155529 PubMedCrossRefGoogle Scholar
  281. Tari LW, Li X, Trzoss M et al (2013) Tricyclic GyrB/ParE (TriBE) inhibitors: a new class of broad-spectrum dual-targeting antibacterial agents. PLoS ONE 8:e84409. doi: 10.1371/journal.pone.0084409 PubMedPubMedCentralCrossRefGoogle Scholar
  282. Taubes G (2008) The bacterial fight back. Science 321:356–361PubMedCrossRefGoogle Scholar
  283. Tegos GP, Haynes M, Strouse JJ et al (2011) Microbial efflux pump inhibition: tactics and strategies. Curr Pharm Des 17:1291–1302. doi: 10.1038/nature11130.Reduced PubMedPubMedCentralCrossRefGoogle Scholar
  284. Terlain B, Thomas JP (1969) C R Hebd Seances Acad Sci Ser C 269:1546–1549Google Scholar
  285. Terlain B, Thomas JP (1971a) Bull Chim Soc Fr 6:2349–2356Google Scholar
  286. Terlain B, Thomas JP (1971b) Bull Chim Soc Fr 6:2357–2362Google Scholar
  287. Tettelin H, Riley D, Cattuto C, Medini D (2008) Comparative genomics: the bacterial pan-genome. Curr Opin Microbiol 11:472–477. doi: 10.1016/j.mib.2008.09.006 PubMedCrossRefGoogle Scholar
  288. ‘t Hart P, Oppedijk SF, Breukink E, Martin NI (2016) New insights into nisin’s antibacterial mechanism revealed by binding studies with synthetic lipid II analogues. Biochemistry 55:232–237. doi: 10.1021/acs.biochem.5b01173
  289. Thaker M, Spanogiannopoulos P, Wright GD (2010) The tetracycline resistome. Cell Mol Life Sci 67:419–431. doi: 10.1007/s00018-009-0172-6 PubMedCrossRefGoogle Scholar
  290. Tommasi R, Brown DG, Walkup GK et al (2015) ESKAPEing the labyrinth of antibacterial discovery. Nat Rev Drug Discov 14:529–542. doi: 10.1038/nrd4572 PubMedCrossRefGoogle Scholar
  291. Torres C (2010) Up against the wall. Nat Med 16:628–631. doi: 10.1038/nm0610-628 PubMedCrossRefGoogle Scholar
  292. Toussaint KA, Gallagher JC (2015) β-Lactam/β-lactamase inhibitor combinations: from then to now. Ann Pharmacother 49:86–98. doi: 10.1177/1060028014556652 PubMedCrossRefGoogle Scholar
  293. Upadhyay A, Upadhyaya I, Kollanoor-Johny A, Venkitanarayanan K (2014) Combating pathogenic microorganisms using plant-derived antimicrobials: a minireview of the mechanistic basis. Biomed Res Int Article ID 761741. doi: 10.1155/2014/761741
  294. Uria-Nickelsen M, Neckermann G, Sriram S et al (2013) Novel topoisomerase inhibitors: microbiological characterisation and in vivo efficacy of pyrimidines. Int J Antimicrob Agents 41:363–371. doi: 10.1016/j.ijantimicag.2012.12.001 PubMedCrossRefGoogle Scholar
  295. Venter H, Mowla R, Ohene-Agyei T, Ma S (2015) RND-type drug efflux pumps from Gram-negative bacteria: molecular mechanism and inhibition. Front Microbiol 6:377. doi: 10.3389/fmicb.2015.00377 PubMedPubMedCentralCrossRefGoogle Scholar
  296. Ventola CL (2015) The antibiotic resistance crisis: part 1: causes and threats. P & T 40:277–283Google Scholar
  297. Vivien E, Pitorre D, Cociancich S et al (2007) Heterologous production of albicidin: a promising approach to overproducing and characterizing this potent inhibitor of DNA gyrase. Antimicrob Agents Chemother 51:1549–1552. doi: 10.1128/AAC.01450-06 PubMedPubMedCentralCrossRefGoogle Scholar
  298. Wang JC (2002) Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol 3:430–440. doi: 10.1038/nrm831 PubMedCrossRefGoogle Scholar
  299. Wang H, Gill CJ, Lee SH et al (2013) Discovery of wall teichoic acid inhibitors as potential anti-MRSA beta-lactam combination agents. Chem Biol 20:272–284. doi: 10.1016/j.chembiol.2012.11.013 PubMedPubMedCentralCrossRefGoogle Scholar
  300. Wang W, Qiu Z, Tan H, Cao L (2014) Siderophore production by actinobacteria. Biometals 27:623–631. doi: 10.1007/s10534-014-9739-2 PubMedCrossRefGoogle Scholar
  301. Watanakunakorn C (1984) Mode of action and in-vitro activity of vancomycin. J Antimicrob Chemother 14:7–18. doi: 10.1093/jac/14.suppl_D.7 PubMedCrossRefGoogle Scholar
  302. Wattal C, Goel N (2011) Tackling antibiotic resistance. Nat Rev Microbiol 9:894–896. doi: 10.1038/nrmicro2693 CrossRefGoogle Scholar
  303. Whitman WB, Coleman DC, Wiebe WJ (1998) Prokaryotes: the unseen majority. Proc Natl Acad Sci USA 95:6578–6583. doi: 10.1073/pnas.95.12.6578 PubMedPubMedCentralCrossRefGoogle Scholar
  304. Wiedemann I, Breukink E, Van Kraaij C et al (2001) Specific binding of nisin to the peptidoglycan precursor lipid II combines pore formation and inhibition of cell wall biosynthesis for potent antibiotic activity. J Biol Chem 276:1772–1779. doi: 10.1074/jbc.M006770200 PubMedCrossRefGoogle Scholar
  305. Wijffels G, Dalrymple BP, Prosselkov P et al (2004) Inhibition of protein interactions with the beta 2 sliding clamp of Escherichia coli DNA polymerase III by peptides from beta 2-binding proteins. Biochemistry 43:5661–5671. doi: 10.1021/bi036229j PubMedCrossRefGoogle Scholar
  306. Wijffels G, Johnson WM, Oakley AJ et al (2011) Binding inhibitors of the bacterial sliding clamp by design. J Med Chem 54:4831–4838. doi: 10.1021/jm2004333 PubMedCrossRefGoogle Scholar
  307. Williams DH, Bardsley B (1999) The vancomycin group of antibiotics and the fight against resistant bacteria. Angew Chem Int Ed 38:1172–1193. doi: 10.1002/(SICI)1521-3773(19990503)38:9<1172:AID-ANIE1172>3.0.CO;2-C CrossRefGoogle Scholar
  308. Wolff P, Amal I, Oliéric V et al (2014) Differential modes of peptide binding onto replicative sliding clamps from various bacterial origins. J Med Chem 57:7565–7576. doi: 10.1021/jm500467a PubMedCrossRefGoogle Scholar
  309. Wright GD (2007) The antibiotic resistome: the nexus of chemical and genetic diversity. NatRevMicrobiol 5:175–186. doi: 10.1038/nrmicro1614 Google Scholar
  310. Wright GD (2010) The antibiotic resistome. Exp Opin Drug Disc 5:779–788. doi: 10.1517/17460441.2010.497535 CrossRefGoogle Scholar
  311. Wright GD (2012) The origins of antibiotic resistance. In: Coates ARM (ed) Handbook of experimental pharmacology, pp 45–65Google Scholar
  312. Wright G (2015a) An irresistible newcomer. Nature 517:442–443. doi: 10.1038/nature14193 PubMedCrossRefGoogle Scholar
  313. Wright GD (2015b) Solving the antibiotic crisis. ACS Infect Dis 1:80–84. doi: 10.1021/id500052s PubMedCrossRefGoogle Scholar
  314. Wright GD, Poinar H (2012) Antibiotic resistance is ancient: implications for drug discovery. Trends Microbiol 20:157–159. doi: 10.1016/j.tim.2012.01.002 PubMedCrossRefGoogle Scholar
  315. Wright PM, Seiple IB, Myers AG (2014) The evolving role of chemical synthesis in antibacterial drug discovery. Angew Chem Int Ed 53:8840–8869. doi: 10.1002/anie.201310843 CrossRefGoogle Scholar
  316. Wyke AW, Ward JB, Hayes MV, Curtis NAC (1981) A role in vivo for penicillin-binding protein-4 of Staphylococcus aureus. Eur J Biochem 119:389–393. doi: 10.1111/j.1432-1033.1981.tb05620.x PubMedCrossRefGoogle Scholar
  317. Xu Z-Q, Flavin MT, Flavin J (2014a) Combating multidrug-resistant Gram-negative bacterial infections. Expert Opin Investig Drugs 23:163–182. doi: 10.1517/13543784.2014.848853 PubMedCrossRefGoogle Scholar
  318. Xu Z-Q, Flavin MT, Flavin J (2014b) Combating multidrug-resistant Gram-negative bacterial infections. Expert Opin Investig Drugs 23:163–182. doi: 10.1517/13543784.2014.848853 PubMedCrossRefGoogle Scholar
  319. Yahav D, Farbman L, Leibovici L, Paul M (2011) Colistin: new lessons on an old antibiotic: EBSCOhost. Clin Microbiol Infect 18:18–29CrossRefGoogle Scholar
  320. Yin Z, Wang Y, Whittell LR et al (2014a) DNA replication is the target for the antibacterial effects of nonsteroidal anti-inflammatory drugs. Chem Biol 21:481–487. doi: 10.1016/j.chembiol.2014.02.009 PubMedCrossRefGoogle Scholar
  321. Yin Z, Whittell LR, Wang Y et al (2014b) Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach. J Med Chem 57:2799–2806. doi: 10.1021/jm500122r PubMedCrossRefGoogle Scholar
  322. Yin Z, Whittell LR, Wang Y et al (2015) Bacterial sliding clamp inhibitors that mimic the sequential binding mechanism of endogenous linear motifs. J Med Chem 58:4693–4702. doi: 10.1021/acs.jmedchem.5b00232 PubMedCrossRefGoogle Scholar
  323. Yoshida H, Bogaki M, Nakamura M, Nakamura S (1990) Quinolone resistance-determining region in the DNA gyrase gyrA gene of Escherichia coli. Antimicrob Agents Chemother 34:1271–1272. doi: 10.1128/aac.34.6.1271 PubMedPubMedCentralCrossRefGoogle Scholar
  324. Yoshida H, Bogaki M, Nakamura M et al (1991) Quinolone resistance-determining region in the DNA gyrase gyrB gene of Escherichia coli. Antimicrob Agents Chemother 35:1647–1650. doi: 10.1128/AAC.35.8.1647 PubMedPubMedCentralCrossRefGoogle Scholar
  325. Young IG (1975) Biosynthesis of bacterial menaquinones. Menaquinone mutants of Escherichia coli. Biochemistry 14:399–406. doi: 10.1021/bi00673a029 PubMedCrossRefGoogle Scholar
  326. Yunis AA (1988) Chloramphenicol: relation of structure to activity and toxicity. Annu Rev Pharmacol Toxicol 28:83–100 doi:10.1146/annurev.pa.28.040188.000503PubMedCrossRefGoogle Scholar
  327. Zaffiri L, Gardner J, Toledo-Pereyra LH (2012) History of antibiotics. From salvarsan to cephalosporins. J Invest Surg 25:67–77. doi: 10.3109/08941939.2012.664099 PubMedCrossRefGoogle Scholar
  328. Zapun A, Philippe J, Abrahams KA et al (2013) In vitro reconstitution of peptidoglycan assembly from the gram-positive pathogen streptococcus pneumoniae. ACS Chem Biol 8:2688–2696. doi: 10.1021/cb400575t PubMedCrossRefGoogle Scholar
  329. Zetts R (2014) Report of the Antibiotics resistance project: antibiotics currently in clinical development. http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-development
  330. Zgurskaya HI, López CA, Gnanakaran S (2015) Permeability barrier of Gram-negative cell envelopes and approaches to bypass it. ACS Infect Dis 1:512–522. doi: 10.1021/acsinfecdis.5b00097 PubMedPubMedCentralCrossRefGoogle Scholar
  331. Zhanel GG, Walkty AJ, Karlowsky JA (2015) Fidaxomicin: a novel agent for the treatment of clostridium difficile infection. Can J Infect Dis Med Microbiol 26:305–313PubMedPubMedCentralGoogle Scholar
  332. Zhang G, Meredith TC, Kahne D (2013) On the essentiality of lipopolysaccharide to Gram-negative bacteria. Curr Opin Microbiol 16:779–785. doi: 10.1016/j.mib.2013.09.007 PubMedPubMedCentralCrossRefGoogle Scholar
  333. Zhao M, Goedecke T, Gunn J, et al (2013) Protostane and fusidane triterpenes: a mini-review. Molecules 18:4054–4080. doi: 10.3390/molecules18044054

Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  1. 1.Department of Chemical BiologyHelmholtz Centre for Infection ResearchBraunschweigGermany

Personalised recommendations