Advertisement

Strategies for Circumventing Bacterial Resistance Mechanisms

  • Jed F. FisherEmail author
  • Jarrod W. Johnson
  • Shahriar Mobashery
Reference work entry

Abstract

The future practices for the control of bacterial infections are uncertain. The intransigent infection is no longer found just among the immune compromised but is now found both in and out the boundaries of the hospital. Preserving the efficacy of the antibacterials we have, in order to secure the time needed to discover and develop new antibacterials, will require abrupt change: in the way antibacterials are dispensed and disposed, in the criteria used to measure clinical safety and efficacy, in the financial incentives for antibacterial development, and in the understanding of the molecular mechanisms governing the relationship between the antibacterial and the bacterium. This review examines this relationship from the particular perspective of the eventual need to circumvent resistance mechanisms in order to reclaim the lifesaving value of the antibacterial chemical.

Keywords

Antibiotic Cell Wall Cytoskeleton Natural Products Resistome Synergy 

References

  1. Abranches J, Tijerina P, Aviles-Reyes A, Gaca AO, Kajfasz JK, Lemos JA (2013) The cell wall-targeting antibiotic stimulon of Enterococcus faecalis. PLoS One 8:e64875. doi:10.1371/journal.pone.0064875PubMedPubMedCentralCrossRefGoogle Scholar
  2. Agarwal AK, Fishwick CWG (2010) Structure-based design of anti-infectives. Ann NY Acad Sci 1213:20–45. doi:10.1111/j.1749-6632.2010.05859.xPubMedCrossRefGoogle Scholar
  3. Ahmed S, Craney A, Pimentel-Elardo SM, Nodwell JR (2013) A synthetic, species-specific activator of secondary metabolism and sporulation in Streptomyces coelicolor. ChemBioChem 14:83–91. doi:10.1002/cbic.201200619PubMedCrossRefGoogle Scholar
  4. Allen HK, Levine UY, Looft T, Bandrick M, Casey TA (2013) Treatment, promotion, commotion: antibiotic alternatives in food-producing animals. Trends Microbiol 21:114–119. doi:10.1016/j.tim.2012.11.001PubMedCrossRefGoogle Scholar
  5. Aluotto S, Tynan H, Maggio C, Falzone M, Mukherjee A, Gullo V, Demain AL (2013) Development of a semi-defined medium supporting production of platensimycin and platencin by Streptomyces platensis. J Antibiot (Tokyo) 66:51–54. doi:10.1038/ja.2012.97CrossRefGoogle Scholar
  6. Amoroso A, Boudet J, Berzigotti S, Duval S, Teller N, Mengin-Lecreulx D, Luxen A, Simorre J-P, Joris B (2012) A peptidoglycan fragment triggers β-lactam resistance in Bacillus licheniformis. PLoS Pathog 8:e1002571. doi:10.1371/journal.ppat.1002571PubMedPubMedCentralCrossRefGoogle Scholar
  7. Andersen MR, Nielsen JB, Klitgaard A, Petersen LM, Zachariasen M, Hansen TJ, Blicher LH, Gotfredsen CH, Larsen TO, Nielsen KF, Mortensen UH (2013) Accurate prediction of secondary metabolite gene clusters in filamentous fungi. Proc Natl Acad Sci U S A 110:E99–E107. doi:10.1073/pnas.1205532110PubMedCrossRefGoogle Scholar
  8. Anderson DE, Kim MB, Moore JT, O’Brien TE, Sorto NA, Grove CI, Lackner LL, Ames JB, Shaw JT (2012) Comparison of small molecule inhibitors of the bacterial cell division protein FtsZ and Identification of a reliable cross-species inhibitor. ACS Chem Biol 7:1918–1928. doi:10.1021/cb300340jPubMedPubMedCentralCrossRefGoogle Scholar
  9. Arede P, Ministro J, Oliveira DC (2013) Redefining the role of the β-lactamase locus in methicillin-resistant Staphylococcus aureus: β-lactamase regulators disrupt the MecI-mediated strong repression on mecA and optimize the phenotypic expression of resistance in strains with constitutive mecA expression. Antimicrob Agents Chemother 57:3037–3045. doi:10.1128/AAC. 02621-12PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bald D, Koul A (2013) Advances and strategies in discovery of new antibacterials for combating metabolically resting bacteria. Drug Discov Today 18:250–255. doi:10.1016/j.drudis.2012.09.007PubMedCrossRefGoogle Scholar
  11. Balemans W, Vranckx L, Lounis N, Pop O, Guillemont J, Vergauwen K, Mol S, Gilissen R, Motte M, Lancois D, De Bolle M, Bonroy K, Lill H, Andries K, Bald D, Koul A (2012) Novel antibiotics targeting respiratory ATP synthesis in gram-positive pathogenic bacteria. Antimicrob Agents Chemother 56:4131–4139. doi:10.1128/AAC. 00273-12PubMedPubMedCentralCrossRefGoogle Scholar
  12. Baltz RH (2014) Combinatorial biosynthesis of cyclic lipopeptide antibiotics: a model for synthetic biology to accelerate the evolution of secondary metabolite biosynthetic pathways. ACS Synth Biol 3:748–758. doi:10.1021/sb3000673PubMedCrossRefGoogle Scholar
  13. Bara R, Zerfass I, Aly AH, Goldbach-Gecke H, Raghavan V, Sass P, Mándi A, Wray V, Polavarapu PL, Pretsch A, Lin W, Kurtán T, Debbab A, Brötz-Oesterhelt H, Proksch P (2013) Atropisomeric dihydroanthracenones as inhibitors of multiresistant Staphylococcus aureus. J Med Chem 56:3257–3272. doi:10.1021/jm301816aPubMedCrossRefGoogle Scholar
  14. Barreteau H, Kovac A, Boniface A, Sova M, Gobec S, Blanot D (2008) Cytoplasmic steps of peptidoglycan biosynthesis. FEMS Microbiol Rev 32:168–207. doi:10.1111/j.1574-6976.2008.00104.xPubMedCrossRefGoogle Scholar
  15. Bartlett JG, Gilbert DN, Spellberg B (2013) Seven ways to preserve the miracle of antibiotics. Clin Infect Dis 56:1445–1450. doi:10.1093/cid/cit070PubMedCrossRefGoogle Scholar
  16. Beceiro A, Tomás M, Bou G (2013) Antimicrobial resistance and virulence: a successful or deleterious association in the bacterial world? Clin Microbiol Rev 26:185–230. doi:10.1128/CMR. 00059-12PubMedPubMedCentralCrossRefGoogle Scholar
  17. Becker B, Cooper MA (2013) Aminoglycoside antibiotics in the 21st century. ACS Chem Biol 8:105–115. doi:10.1021/cb3005116PubMedCrossRefGoogle Scholar
  18. Berdy J (2012) Thoughts and facts about antibiotics: where we are now and where we are heading. J Antibiot (Tokyo) 65:385–395. doi:10.1038/ja.2012.27CrossRefGoogle Scholar
  19. Bertrand S, Schumpp O, Bohni N, Monod M, Gindro K, Wolfender J-L (2013) De novo production of metabolites by fungal co-culture of Trichophyton rubrum and Bionectria ochroleuca. J Nat Prod 76:1157–1165. doi:10.1021/np400258fPubMedCrossRefGoogle Scholar
  20. Bertsche U, Yang SJ, Kuehner D, Wanner S, Mishra NN, Roth T, Nega M, Schneider A, Mayer C, Grau T, Bayer AS, Weidenmaier C (2013) Increased cell wall teichoic acid production and D-alanylation are common phenotypes among daptomycin-resistant MRSA clinical isolates. PLoS One 8:e67398. doi:10.1371/journal.pone.0067398PubMedPubMedCentralCrossRefGoogle Scholar
  21. Blackledge MS, Worthington RJ, Melander C (2013) Biologically inspired strategies for combating bacterial biofilms. Curr Opin Pharmacol 13:699–706. doi:10.1016/j.coph.2013.07.004PubMedPubMedCentralCrossRefGoogle Scholar
  22. Bodro M, Sabe N, Tubau F, Llado L, Baliellas C, Roca J, Cruzado JM, Carratala J (2013) Risk factors and outcomes of bacteremia caused by drug-resistant ESKAPE pathogens in solid-organ transplant recipients. Transplantation 96:843–849. doi:10.1097/TP.0b013e3182a049fdPubMedCrossRefGoogle Scholar
  23. Bogan C, Marchaim D (2013) The role of antimicrobial stewardship in curbing carbapenem resistance. Future Microbiol 8:979–991. doi:10.2217/fmb.13.73PubMedCrossRefGoogle Scholar
  24. Bologa CG, Ursu O, Oprea TI, Melançon CE III, Tegos GP (2013) Emerging trends in the discovery of natural product antibacterials. Curr Opin Pharmacol 13:678–687. doi:10.1016/j.coph.2013.07.002PubMedPubMedCentralCrossRefGoogle Scholar
  25. Boucher HW, Talbot GH, Benjamin DK Jr, Bradley J, Guidos RJ, Jones RN, Murray BE, Bonomo RA, Gilbert D (2013) 10 × ‘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/cit152PubMedPubMedCentralCrossRefGoogle Scholar
  26. Bow EJ (2013) There should be no ESKAPE for febrile neutropenic cancer patients: the dearth of effective antibacterial drugs threatens anticancer efficacy. J Antimicrob Chemother 68:492–495. doi:10.1093/jac/dks512PubMedCrossRefGoogle Scholar
  27. Breitling R, Achcar F, Takano E (2013) Modeling challenges in the synthetic biology of secondary metabolism. ACS Synth Biol 2:373–378. doi:10.1021/sb4000228PubMedCrossRefGoogle Scholar
  28. Brown MF, Reilly U, Abramite JA, Arcari JT, Oliver R, Barham RA, Che Y, Chen JM, Collantes EM, Chung SW, Desbonnet C, Doty J, Doroski M, Engtrakul JJ, Harris TM, Huband M, Knafels JD, Leach KL, Liu S, Marfat A, Marra A, McElroy E, Melnick M, Menard CA, Montgomery JI, Mullins L, Noe MC, O’Donnell J, Penzien J, Plummer MS, Price LM, Shanmugasundaram V, Thoma C, Uccello DP, Warmus JS, Wishka DG (2012a) Potent inhibitors of LpxC for the treatment of gram-negative infections. J Med Chem 55:914–923. doi:10.1021/jm2014748PubMedCrossRefGoogle Scholar
  29. Brown S, Xia G, Luhachack LG, Campbell J, Meredith TC, Chen C, Winstel V, Gekeler C, Irazoqui JE, Peschel A, Walker S (2012b) Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids. Proc Natl Acad Sci U S A 109:18909–18914. doi:10.1073/pnas.1209126109PubMedPubMedCentralCrossRefGoogle Scholar
  30. Brown S, Santa Maria JPJ, Walker S (2013) Wall teichoic acids of gram-positive bacteria. Annu Rev Microbiol 67:313–336. doi:10.1146/annurev-micro-092412-155620PubMedCrossRefGoogle Scholar
  31. 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.2013.12.059PubMedCrossRefGoogle Scholar
  32. Brynildsen MP, Winkler JA, Spina CS, Macdonald IC, Collins JJ (2013) Potentiating antibacterial activity by predictably enhancing endogenous microbial ROS production. Nat Biotechnol 31:160–165. doi:10.1038/nbt.2458PubMedPubMedCentralCrossRefGoogle Scholar
  33. Bugg TDH (2014) Editorial: antibacterial targets for the 21st century. Bioorg Chem 55:1. doi:10.1016/j.bioorg.2014.05.005PubMedCrossRefGoogle Scholar
  34. Bush K (2012) Improving known classes of antibiotics: an optimistic approach for the future. Curr Opin Pharmacol 12:527–534. doi:10.1016/j.coph.2012.06.003PubMedCrossRefGoogle Scholar
  35. Butler MS, Blaskovich MA, Cooper MA (2013) Antibiotics in the clinical pipeline in 2013. J Antibiot (Tokyo) 66:571–591. doi:10.1038/ja.2013.86CrossRefGoogle Scholar
  36. Campbell J, Singh AK, Swoboda JG, Gilmore MS, Wilkinson BJ, Walker S (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. 05938-11PubMedPubMedCentralCrossRefGoogle Scholar
  37. Carattoli A (2013) Plasmids and the spread of resistance. Int J Med Microbiol 303:298–304. doi:10.1016/j.ijmm.2013.02.001PubMedCrossRefGoogle Scholar
  38. Cavallari JF, Lamers RP, Scheurwater EM, Matos AL, Burrows LL (2013) Changes to Its peptidoglycan-remodeling enzyme repertoire modulate β-lactam resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 57:3078–3084. doi:10.1128/AAC. 00268-13PubMedPubMedCentralCrossRefGoogle Scholar
  39. Celler K, Koning RI, Koster AJ, van Wezel GP (2013) Multidimensional view of the bacterial cytoskeleton. J Bacteriol 195:1627–1636. doi:10.1128/JB.02194-12PubMedPubMedCentralCrossRefGoogle Scholar
  40. Chang CJ, Lin JH, Chang KC, Lai MJ, Rohini R, Hu A (2013) Diagnosis of β-lactam resistance in Acinetobacter baumannii using shotgun proteomics and LC-nano-ESI ion trap MS. Anal Chem 85:2802–2808. doi:10.1021/ac303326aPubMedCrossRefGoogle Scholar
  41. Chatterjee A, Cook LCC, Shu C-C, Chen Y, Manias DA, Ramkrishna D, Dunny GM, Hu W-S (2013) Antagonistic self-sensing and mate-sensing signaling controls antibiotic-resistance transfer. Proc Natl Acad Sci U S A 110:7086–7090. doi:10.1073/pnas.1212256110PubMedPubMedCentralCrossRefGoogle Scholar
  42. Chopra I (2013) The 2012 Garrod lecture: discovery of antibacterial drugs in the 21st century. J Antimicrob Chemother 68:496–505. doi:10.1093/jac/dks436PubMedCrossRefGoogle Scholar
  43. Ciccolini M, Donker T, Köck R, Mielke M, Hendrix R, Jurke A, Rahamat-Langendoen J, Becker K, Niesters HGM, Grundmann H, Friedrich AW (2013) Infection prevention in a connected world: the case for a regional approach. Int J Med Microbiol 303:380–387. doi:10.1016/j.ijmm.2013.02.003PubMedCrossRefGoogle Scholar
  44. Clark RB, Hunt DK, He M, Achorn C, Chen CL, Deng Y, Fyfe C, Grossman TH, Hogan PC, O’Brien WJ, Plamondon L, Ronn M, Sutcliffe JA, Zhu Z, Xiao XY (2012) Fluorocyclines. 2. Optimization of the C-9 side-chain for antibacterial activity and oral efficacy. J Med Chem 55:606–622. doi:10.1021/jm201467rPubMedCrossRefGoogle Scholar
  45. Cohen J (2013) Confronting the threat of multidrug-resistant gram-negative bacteria in critically ill patients. J Antimicrob Chemother 68:490–491. doi:10.1093/jac/dks460PubMedCrossRefGoogle Scholar
  46. Cohen NR, Lobritz MA, Collins JJ (2013) Microbial persistence and the road to drug resistance. Cell Host Microbe 13:632–642. doi:10.1016/j.chom.2013.05.009PubMedPubMedCentralCrossRefGoogle Scholar
  47. Commichau FM, Pietack N, Stulke J (2013) Essential genes in Bacillus subtilis: a re-evaluation after ten years. Mol Biosyst 9:1068–1075. doi:10.1039/c3mb25595fPubMedCrossRefGoogle Scholar
  48. Conlon BP, Nakayasu ES, Fleck LE, LaFleur MD, Isabella VM, Coleman K, Leonard SN, Smith RD, Adkins JN, Lewis K (2013) Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature 503:365–370. doi:10.1038/nature12790PubMedPubMedCentralCrossRefGoogle Scholar
  49. Cox G, Wright GD (2013) Intrinsic antibiotic resistance: mechanisms, origins, challenges and solutions. Int J Med Microbiol 303:287–292. doi:10.1016/j.ijmm.2013.02.009PubMedCrossRefGoogle Scholar
  50. Craney A, Ahmed S, Nodwell J (2013) Towards a new science of secondary metabolism. J Antibiot (Tokyo) 66:387–400. doi:10.1038/ja.2013.25CrossRefGoogle Scholar
  51. Dalhoff A, Weintraub A, Nord CE (2014) Alternative strategies for proof-of-principle studies of antibacterial agents. Antimicrob Agents Chemother 58:4257–4263. doi:10.1128/AAC. 02473-14PubMedPubMedCentralCrossRefGoogle Scholar
  52. Davies J (2013) Specialized microbial metabolites: functions and origins. J Antibiot (Tokyo) 66:361–364. doi:10.1038/ja.2013.61CrossRefGoogle Scholar
  53. Davies J (2014) The origin and evolution of antibiotics. In: Antimicrobials: new and old molecules in the fight against multi-resistant bacteria. Springer, Heidelberg, pp 3–10. doi:10.1007/978-3-642-39968-8_1CrossRefGoogle Scholar
  54. Davies SC, Fowler T, Watson J, Livermore DM, Walker D (2013) Annual report of the chief medical officer: Infection and the rise of antimicrobial resistance. Lancet 381:1606–1609. doi:10.1016/S0140-6736(13)60604-2PubMedCrossRefGoogle Scholar
  55. Derewacz DK, Goodwin CR, McNees CR, McLean JA, Bachmann BO (2013) Antimicrobial drug resistance affects broad changes in metabolomic phenotype in addition to secondary metabolism. Proc Natl Acad Sci U S A 110:2336–2341. doi:10.1073/pnas.1218524110PubMedPubMedCentralCrossRefGoogle Scholar
  56. Dhand A, Bayer AS, Pogliano J, Yang SJ, Bolaris M, Nizet V, Wang G, Sakoulas G (2011) Use of antistaphylococcal β-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: role of enhanced daptomycin binding. Clin Infect Dis 53:158–163. doi:10.1093/cid/cir340PubMedPubMedCentralCrossRefGoogle Scholar
  57. Drawz SM, Bonomo RA (2010) Three decades of β-lactamase inhibitors. Clin Microbiol Rev 23:160–201. doi:10.1128/CMR. 00037-09PubMedPubMedCentralCrossRefGoogle Scholar
  58. Duffield M, Cooper I, McAlister E, Bayliss M, Ford D, Oyston P (2010) Predicting conserved essential genes in bacteria: in silico identification of putative drug targets. Mol Biosyst 6:2482–2489. doi:10.1039/c0mb00001aPubMedCrossRefGoogle Scholar
  59. East SP, Silver LL (2013) Multitarget ligands in antibacterial research: progress and opportunities. Expert Opin Drug Discov 8:143–156. doi:10.1517/17460441.2013.743991PubMedCrossRefGoogle Scholar
  60. Egan AJ, Vollmer W (2013) The physiology of bacterial cell division. Ann N Y Acad Sci 1277:8–28. doi:10.1111/j.1749-6632.2012.06818.xPubMedCrossRefGoogle Scholar
  61. El-Elimat T, Figueroa M, Ehrmann BM, Cech NB, Pearce CJ, Oberlies NH (2013) High-resolution MS, MS/MS, and UV database of fungal secondary metabolites as a dereplication protocol for bioactive natural products. J Nat Prod 76:1709–1716. doi:10.1021/np4004307PubMedCrossRefGoogle Scholar
  62. Elsen NL, Lu J, Parthasarathy G, Reid JC, Sharma S, Soisson SM, Lumb KJ (2012) Mechanism of action of the cell-division inhibitor PC190723: modulation of FtsZ assembly cooperativity. J Am Chem Soc 134:12342–12345. doi:10.1021/ja303564aPubMedCrossRefGoogle Scholar
  63. Eun YJ, Zhou M, Kiekebusch D, Schlimpert S, Trivedi RR, Bakshi S, Zhong Z, Wahlig TA, Thanbichler M, Weibel DB (2013) Divin: a small molecule inhibitor of bacterial divisome assembly. J Am Chem Soc 135:9768–9776. doi:10.1021/ja404640fPubMedPubMedCentralCrossRefGoogle Scholar
  64. Ezraty B, Vergnes A, Banzhaf M, Duverger Y, Huguenot A, Brochado AR, Su SY, Espinosa L, Loiseau L, Py B, Typas A, Barras F (2013) Fe-S cluster biosynthesis controls uptake of aminoglycosides in a ROS-less death pathway. Science 340:1583–1587. doi:10.1126/science.1238328PubMedCrossRefGoogle Scholar
  65. Farha MA, Leung A, Sewell EW, D’Elia MA, Allison SE, Ejim L, Pereira PM, Pinho MG, Wright GD, Brown ED (2013a) 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/cb300413mPubMedCrossRefGoogle Scholar
  66. Farha MA, Verschoor CP, Bowdish D, Brown ED (2013b) Collapsing the proton motive force to identify synergistic combinations against Staphylococcus aureus. Chem Biol 20:1168–1178. doi:10.1016/j.chembiol.2013.07.006PubMedCrossRefGoogle Scholar
  67. Fernández A, Pérez A, Ayala JA, Mallo S, Rumbo-Feal S, Tomás M, Poza M, Bou G (2012) Expression of OXA-Type and SFO-1 β-lactamases Induces changes in peptidoglycan composition and affects bacterial fitness. Antimicrob Agents Chemother 56:1877–1884. doi:10.1128/AAC. 05402-11PubMedPubMedCentralCrossRefGoogle Scholar
  68. Fernández L, Álvarez-Ortega C, Wiegand I, Olivares J, Kocíncová D, Lam JS, Martínez JL, Hancock REW (2013) Characterization of the polymyxin B resistome of Pseudomonas aeruginosa. Antimicrob Agents Chemother 57:110–119. doi:10.1128/AAC. 01583-12PubMedPubMedCentralCrossRefGoogle Scholar
  69. Finley RL, Collignon P, Larsson DGJ, McEwen SA, Li XZ, Gaze WH, Reid-Smith R, Timinouni M, Graham DW, Topp E (2013) The scourge of antibiotic resistance: the important role of the environment. Clin Infect Dis 57:704–710. doi:10.1093/cid/cit355PubMedCrossRefGoogle Scholar
  70. Fonvielle M, Li de La Sierra-Gallay I, El-Sagheer AH, Lecerf M, Patin D, Mellal D, Mayer C, Blanot D, Gale N, Brown T, van Tilbeurgh H, Ethève-Quelquejeu M, Arthur M (2013) The structure of FemXWv in complex with a peptidyl-RNA conjugate: mechanism of aminoacyl transfer from Ala-tRNA(Ala) to peptidoglycan precursors. Angew Chem Int Ed 52:7278–7281. doi:10.1002/anie.201301411CrossRefGoogle Scholar
  71. Foss MH, Eun Y-J, Grove CI, Pauw DA, Sorto NA, Rensvold JW, Pagliarini DJ, Shaw JT, Weibel DB (2013) Inhibitors of bacterial tubulin target bacterial membranes in vivo. Med Chem Comm 4:112–119. doi:10.1039/c2md20127eCrossRefGoogle Scholar
  72. Foucault ML, Depardieu F, Courvalin P, Grillot-Courvalin C (2010) Inducible expression eliminates the fitness cost of vancomycin resistance in enterococci. Proc Natl Acad Sci U S A 107:16964–16969. doi:10.1073/pnas.1006855107PubMedPubMedCentralCrossRefGoogle Scholar
  73. Galán JC, González-Candelas F, Rolain JM, Cantón R (2013) Antibiotics as selectors and accelerators of diversity in the mechanisms of resistance: from the resistome to genetic plasticity in the β-lactamases’ world. Front Microbiol 4:9. doi:10.3389/fmicb.2013.00009PubMedPubMedCentralCrossRefGoogle Scholar
  74. Gammon K (2014) Drug discovery: leaving no stone unturned. Nature 509:S10–S12. doi:10.1038/509S10aPubMedCrossRefGoogle Scholar
  75. Gerdes K, Ingmer H (2013) Antibiotics: killing the survivors. Nature 503:347–349. doi:10.1038/nature12834PubMedCrossRefGoogle Scholar
  76. Gerwick WH, Moore BS (2012) Lessons from the past and charting the future of marine natural products drug discovery and chemical biology. Chem Biol 19:85–98. doi:10.1016/j.chembiol.2011.12.014PubMedPubMedCentralCrossRefGoogle Scholar
  77. Goldberg K, Sarig H, Zaknoon F, Epand RF, Epand RM, Mor A (2013) Sensitization of gram-negative bacteria by targeting the membrane potential. FASEB J 27:3818–3826. doi:10.1096/fj.13-227942PubMedCrossRefGoogle Scholar
  78. Graupner K, Scherlach K, Bretschneider T, Lackner G, Roth M, Gross H, Hertweck C (2012) Imaging mass spectrometry and genome mining reveal highly antifungal virulence factor of mushroom soft rot pathogen. Angew Chem Int Ed 51:13173–13177. doi:10.1002/anie.201206658CrossRefGoogle Scholar
  79. Greenfield LK, Whitfield C (2012) Synthesis of lipopolysaccharide O-antigens by ABC transporter-dependent pathways. Carbohydr Res 356:12–24. doi:10.1016/j.carres.2012.02.027PubMedCrossRefGoogle Scholar
  80. Gupta S, Bram EE, Weiss R (2013) Genetically programmable pathogen sense and destroy. ACS Synth Biol 2:715–723. doi:10.1021/sb4000417PubMedCrossRefGoogle Scholar
  81. Gutierrez A, Laureti L, Crussard S, Abida H, Rodriguez-Rojas A, Blazquez J, Baharoglu Z, Mazel D, Darfeuille F, Vogel J, Matic I (2013) β-Lactam antibiotics promote bacterial mutagenesis via an RpoS-mediated reduction in replication fidelity. Nat Commun 4:1610. doi:10.1038/ncomms2607PubMedPubMedCentralCrossRefGoogle Scholar
  82. Hall CL, Tschannen M, Worthey EA, Kristich CJ (2013) IreB, a Ser/Thr kinase substrate, influences antimicrobial resistance in Enterococcus faecalis. Antimicrob Agents Chemother 57:6179–6686. doi:10.1128/AAC. 01472-13PubMedPubMedCentralCrossRefGoogle Scholar
  83. Händel N, Schuurmans JM, Brul S, ter Kuile BH (2013) Compensation of the metabolic costs of antibiotic resistance by physiological adaptation in Escherichia coli. Antimicrob Agents Chemother 57:3752–3762. doi:10.1128/AAC. 02096-12PubMedPubMedCentralCrossRefGoogle Scholar
  84. Hankins JV, Madsen JA, Giles DK, Brodbelt JS, Trent MS (2012) Amino acid addition to Vibrio cholerae LPS establishes a link between surface remodeling in gram-positive and gram-negative bacteria. Proc Natl Acad Sci U S A 109:8722–8727. doi:10.1073/pnas.1201313109PubMedPubMedCentralCrossRefGoogle Scholar
  85. Harris SR, Cartwright EJ, Torok ME, Holden MT, Brown NM, Ogilvy-Stuart AL, Ellington MJ, Quail MA, Bentley SD, Parkhill J, Peacock SJ (2013) Whole-genome sequencing for analysis of an outbreak of meticillin-resistant Staphylococcus aureus: a descriptive study. Lancet Infect Dis 13:130–136. doi:10.1016/S1473-3099(12)70268-2PubMedPubMedCentralCrossRefGoogle Scholar
  86. Haruki H, Pedersen MG, Gorska KI, Pojer F, Johnsson K (2013) Tetrahydrobiopterin biosynthesis as an off-target of sulfa drugs. Science 340:987–991. doi:10.1126/science.1232972PubMedCrossRefGoogle Scholar
  87. Hasan S, Ali SZ, Khan AU (2013) Novel combinations of antibiotics to inhibit extended-spectrum β-lactamase and metallo-β-lactamase producers in vitro: a synergistic approach. Future Microbiol 8:939–944. doi:10.2217/fmb.13.54PubMedCrossRefGoogle Scholar
  88. Hede K (2014) Antibiotic resistance: an infectious arms race. Nature 509:S2–S3. doi:10.1038/509S2aPubMedCrossRefGoogle Scholar
  89. Hirakawa H, Tomita H (2013) Interference of bacterial cell-to-cell communication: a new concept of antimicrobial chemotherapy breaks antibiotic resistance. Front Microbiol 4:114. doi:10.3389/fmicb.2013.00114PubMedPubMedCentralCrossRefGoogle Scholar
  90. Holt KE, Thieu Nga TV, Thanh DP, Vinh H, Kim DW, Vu Tra MP, Campbell JI, Hoang NV, Vinh NT, Minh PV, Thuy CT, Nga TT, Thompson C, Dung TT, Nhu NT, Vinh PV, Tuyet PT, Phuc HL, Lien NT, Phu BD, Ai NT, Tien NM, Dong N, Parry CM, Hien TT, Farrar JJ, Parkhill J, Dougan G, Thomson NR, Baker S (2013) Tracking the establishment of local endemic populations of an emergent enteric pathogen. Proc Natl Acad Sci U S A 110:17522–17527. doi:10.1073/pnas.1308632110PubMedPubMedCentralCrossRefGoogle Scholar
  91. Hopwood DA (2013) Imaging mass spectrometry reveals highly specific interactions between actinomycetes to activate specialized metabolic gene clusters. MBio 4:e00612–e00613. doi:10.1128/mBio. 00612-13PubMedPubMedCentralCrossRefGoogle Scholar
  92. Howard SJ, Hopwood S, Davies SC (2014) Antimicrobial resistance: a global challenge. Sci Transl Med 6:236ed10. doi:10.1126/scitranslmed.3009315PubMedCrossRefGoogle Scholar
  93. Huang KH, Durand-Heredia J, Janakiraman A (2013) FtsZ ring stability: of bundles, tubules, crosslinks, and curves. J Bacteriol 195:1859–1868. doi:10.1128/JB.02157-12PubMedPubMedCentralCrossRefGoogle Scholar
  94. Huber J, Donald RG, Lee SH, Jarantow LW, Salvatore MJ, Meng X, Painter R, Onishi RH, Occi J, Dorso K, Young K, Park YW, Skwish S, Szymonifka MJ, Waddell TS, Miesel L, Phillips JW, Roemer T (2009) Chemical genetic identification of peptidoglycan inhibitors potentiating carbapenem activity against methicillin-resistant Staphylococcus aureus. Chem Biol 16:837–848. doi:10.1016/j.chembiol.2009.05.012PubMedCrossRefGoogle Scholar
  95. Imamovic L, Sommer MOA (2013) Use of collateral sensitivity networks to design drug cycling protocols that avoid resistance development. Sci Transl Med 5:204ra132. doi:10.1126/scitranslmed.3006609Google Scholar
  96. Imperi F, Massai F, Facchini M, Frangipani E, Visaggio D, Leoni L, Bragonzi A, Visca P (2013a) Repurposing the antimycotic drug flucytosine for suppression of Pseudomonas aeruginosa pathogenicity. Proc Natl Acad Sci U S A 110:7458–7463. doi:10.1073/pnas.1222706110PubMedPubMedCentralCrossRefGoogle Scholar
  97. Imperi F, Massai F, Pillai CR, Longo F, Zennaro E, Rampioni G, Visca P, Leoni L (2013b) New life for an old drug: the anthelmintic drug niclosamide inhibits Pseudomonas aeruginosa quorum sensing. Antimicrob Agents Chemother 57:996–1005. doi:10.1128/AAC. 01952-12PubMedPubMedCentralCrossRefGoogle Scholar
  98. Jackman JE, Fierke CA, Tumey LN, Pirrung M, Uchiyama T, Tahir SH, Hindsgaul O, Raetz CRH (2000) Antibacterial agents that target lipid A biosynthesis in gram-negative bacteria. Inhibition of diverse UDP-3-O-(r-3-hydroxymyristoyl)-N-acetylglucosamine deacetylases by substrate analogs containing zinc binding motifs. J Biol Chem 275:11002–11009. doi:10.1074/jbc.275.15.11002PubMedCrossRefGoogle Scholar
  99. Jang KH, Nam SJ, Locke JB, Kauffman CA, Beatty DS, Paul LA, Fenical W (2013) Anthracimycin, a potent anthrax antibiotic from a marine-derived actinomycete. Angew Chem Int Ed 52:7822–7824. doi:10.1002/anie.201302749CrossRefGoogle Scholar
  100. Jiang W, Li B, Zheng X, Liu X, Pan X, Qing R, Cen Y, Zheng J, Zhou H (2013) Artesunate has its enhancement on antibacterial activity of β-lactams via increasing the antibiotic accumulation within methicillin-resistant Staphylococcus aureus (MRSA). J Antibiot (Tokyo) 66:339–345. doi:10.1038/ja.2013.22CrossRefGoogle Scholar
  101. Johnson JW, Fisher JF, Mobashery S (2013) Bacterial cell-wall recycling. Ann N Y Acad Sci 1277:54–75. doi:10.1111/j.1749-6632.2012.06813.xPubMedCrossRefGoogle Scholar
  102. Kalghatgi S, Spina CS, Costello JC, Liesa M, Morones-Ramirez JR, Slomovic S, Molina A, Shirihai OS, Collins JJ (2013) Bactericidal antibiotics induce mitochondrial dysfunction and oxidative damage in mammalian cells. Sci Transl Med 5:192ra85. doi:10.1126/scitranslmed.3006055Google Scholar
  103. Kamen Ek S, Gur-Bertok D (2013) Global transcriptional responses to the bacteriocin colicin M in Escherichia coli. BMC Microbiol 13:42. doi:10.1186/1471-2180-13-42CrossRefGoogle Scholar
  104. Kaneti G, Sarig H, Marjieh I, Fadia Z, Mor A (2013) Simultaneous breakdown of multiple antibiotic resistance mechanisms in S. aureus. FASEB J 27:4834–4843. doi:10.1096/fj.13-237610PubMedCrossRefGoogle Scholar
  105. Kaul M, Mark L, Zhang Y, Parhi AK, LaVoie EJ, Pilch DS (2013) An FtsZ-targeting prodrug with oral antistaphylococcal efficacy in vivo. Antimicrob Agents Chemother 57:5860–5869. doi:10.1128/AAC. 01016-13PubMedPubMedCentralCrossRefGoogle Scholar
  106. Keffer JL, Huecas S, Hammill JT, Wipf P, Andreu JM, Bewley CA (2013) Chrysophaentins are competitive inhibitors of FtsZ and inhibit Z-ring formation in live bacteria. Bioorg Med Chem 21:5673–5678. doi:10.1016/j.bmc.2013.07.033PubMedPubMedCentralCrossRefGoogle Scholar
  107. Kelesidis T, Tewhey R, Humphries RM (2013) Evolution of high-level daptomycin resistance in Enterococcus faecium during daptomycin therapy is associated with limited mutations in the bacterial genome. J Antimicrob Chemother 68:1926–1928. doi:10.1093/jac/dkt117PubMedCrossRefGoogle Scholar
  108. Keren I, Wu Y, Inocencio J, Mulcahy LR, Lewis K (2013) Killing by bactericidal antibiotics does not depend on reactive oxygen species. Science 339:1213–1216. doi:10.1126/science.1232688PubMedCrossRefGoogle Scholar
  109. Khodaverdian V, Pesho M, Truitt B, Bollinger L, Patel P, Nithianantham S, Yu G, Delaney E, Jankowsky E, Shoham M (2013) Discovery of antivirulence agents against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 57:3645–3652. doi:10.1128/AAC. 00269-13PubMedPubMedCentralCrossRefGoogle Scholar
  110. Kim JH, O’Brien KM, Sharma R, Boshoff HI, Rehren G, Chakraborty S, Wallach JB, Monteleone M, Wilson DJ, Aldrich CC, Barry CE III, Rhee KY, Ehrt S, Schnappinger D (2013) A genetic strategy to identify targets for the development of drugs that prevent bacterial persistence. Proc Natl Acad Sci U S A 110:19095–19100. doi:10.1073/pnas.1315860110PubMedPubMedCentralCrossRefGoogle Scholar
  111. Kirst HA (2013) Developing new antibacterials through natural product research. Expert Opin Drug Discov 8:479–493. doi:10.1517/17460441.2013.779666PubMedCrossRefGoogle Scholar
  112. Kohanski MA, Dwyer DJ, Collins JJ (2010) How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol 8:423–435. doi:10.1038/nrmicro2333PubMedPubMedCentralCrossRefGoogle Scholar
  113. Komatsu M, Komatsu K, Koiwai H, Yamada Y, Kozone I, Izumikawa M, Hashimoto J, Takagi M, Omura S, Shin-ya K, Cane DE, Ikeda H (2013) Engineered Streptomyces avermitilis host for heterologous expression of biosynthetic gene cluster for secondary metabolites. ACS Synth Biol 2:384–396. doi:10.1021/sb3001003PubMedPubMedCentralCrossRefGoogle Scholar
  114. Koteva K, Hong HJ, Wang XD, Nazi I, Hughes D, Naldrett MJ, Buttner MJ, Wright GD (2010) A vancomycin photoprobe identifies the histidine kinase VanSsc as a vancomycin receptor. Nat Chem Biol 6:327–329. doi:10.1038/nchembio.350PubMedCrossRefGoogle Scholar
  115. Koyama N, Tokura Y, Munch D, Sahl HG, Schneider T, Shibagaki Y, Ikeda H, Tomoda H (2012) The non-antibiotic small molecule cyslabdan enhances the potency of β-lactams against MRSA by inhibiting pentaglycine interpeptide bridge synthesis. PLoS One 7:e48981. doi:10.1371/journal.pone.0048981PubMedPubMedCentralCrossRefGoogle Scholar
  116. Kumarasiri M, Llarrull LI, Borbulevych O, Fishovitz J, Lastochkin E, Baker BM, Mobashery S (2012) An amino-acid position at the crossroads of evolution of protein function: antibiotic-sensor domain of the BlaR1 protein from Staphylococcus aureus vs. class D β-lactamases. J Biol Chem 287:8232–8241. doi:10.1074/jbc.M111.333179PubMedPubMedCentralCrossRefGoogle Scholar
  117. Kwun MJ, Novotna G, Hesketh AR, Hill L, Hong HJ (2013) In vivo studies suggest that induction of VanS-dependent vancomycin resistance requires binding of the drug to d-Ala-d-Ala termini in the peptidoglycan cell wall. Antimicrob Agents Chemother 57:4470–4480. doi:10.1128/AAC. 00523-13PubMedPubMedCentralCrossRefGoogle Scholar
  118. Lages MC, Beilharz K, Morales Angeles D, Veening JW, Scheffers DJ (2013) The localization of key Bacillus subtilis penicillin binding proteins during cell growth is determined by substrate availability. Environ Microbiol 15:3272–3281. doi:10.1111/1462-2920.12206PubMedCrossRefGoogle Scholar
  119. Laxminarayan R (2014) Antibiotic effectiveness: balancing conservation against innovation. Science 345:1299–1301. doi:10.1126/science.1254163PubMedCrossRefGoogle Scholar
  120. Lázár V, Pal Singh G, Spohn R, Nagy I, Horváth B, Hrtyan M, Busa-Fekete R, Bogos B, Méhi O, Csörgő B, Pósfai G, Fekete G, Szappanos B, Kégl B, Papp B, Pál C (2013) Bacterial evolution of antibiotic hypersensitivity. Mol Syst Biol 9:700. doi:10.1038/msb.2013.57PubMedPubMedCentralCrossRefGoogle Scholar
  121. Le Hello S, Harrois D, Bouchrif B, Sontag L, Elhani D, Guibert V, Zerouali K, Weill FX (2013) Highly drug-resistant Salmonella enterica serotype Kentucky ST198-X1: a microbiological study. Lancet Infect Dis 13:672–679. doi:10.1016/S1473-3099(13)70124-5PubMedCrossRefGoogle Scholar
  122. Lee K, Campbell J, Swoboda JG, Cuny GD, Walker S (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.2010.01.036PubMedPubMedCentralCrossRefGoogle Scholar
  123. Leonard PG, Golemi-Kotra D, Stock AM (2013) Phosphorylation-dependent conformational changes and domain rearrangements in Staphylococcus aureus VraR activation. Proc Natl Acad Sci U S A 110:8525–8530. doi:10.1073/pnas.1302819110PubMedPubMedCentralCrossRefGoogle Scholar
  124. Leuthner KD, Doern GV (2013) Antimicrobial stewardship programs. J Clin Microbiol 51:3916–3920. doi:10.1128/JCM. 01751-13PubMedPubMedCentralCrossRefGoogle Scholar
  125. Lewis K (2013) Platforms for antibiotic discovery. Nat Rev Drug Discov 12:371–387. doi:10.1038/nrd3975PubMedCrossRefGoogle Scholar
  126. Lima TB, Pinto MFS, Ribeiro SM, Alves de Lima L, Viana JC, Júnior NG, de Souza Candido E, Dias SC, Franco OL (2013) Bacterial resistance mechanism: what proteomics can elucidate. FASEB J 27:1291–1303. doi:10.1096/fj.12-221127PubMedCrossRefGoogle Scholar
  127. Liu Y, Imlay JA (2013) Cell death from antibiotics without the involvement of reactive oxygen species. Science 339:1210–1213. doi:10.1126/science.1232751PubMedPubMedCentralCrossRefGoogle Scholar
  128. Livermore DM (2014) Of stewardship, motherhood and apple pie. Int J Antimicrob Agents 43:319–322. doi:10.1016/j.ijantimicag.2014.01.011PubMedCrossRefGoogle Scholar
  129. Llarrull LI, Mobashery S (2012) Dissection of events in the resistance to β-lactam antibiotics mediated by the protein BlaR1 from Staphylococcus aureus. Biochemistry 51:4642–4649. doi:10.1021/bi300429pPubMedPubMedCentralCrossRefGoogle Scholar
  130. Long DR, Mead J, Hendricks JM, Hardy ME, Voyich JM (2013) 18β-Glycyrrhetinic acid inhibits methicillin-resistant Staphylococcus aureus survival and attenuates virulence gene expression. Antimicrob Agents Chemother 57:241–247. doi:10.1128/AAC. 01023-12PubMedPubMedCentralCrossRefGoogle Scholar
  131. Ma S, Ma S (2012) The development of FtsZ inhibitors as potential antibacterial agents. ChemMedChem 7:1161–1172. doi:10.1002/cmdc.201200156PubMedCrossRefGoogle Scholar
  132. Maffioli SI, Fabbretti A, Brandi L, Savelsbergh A, Monciardini P, Abbondi M, Rossi R, Donadio S, Gualerzi CO (2013) Orthoformimycin, a selective inhibitor of bacterial translation elongation from Streptomyces containing an unusual orthoformate. ACS Chem Biol 8:1939–1946. doi:10.1021/cb4004095PubMedCrossRefGoogle Scholar
  133. Mahoney TF, Silhavy TJ (2013) The Cpx stress response confers resistance to some, but not all, bactericidal antibiotics. J Bacteriol 195:1869–1874. doi:10.1128/JB.02197-12PubMedPubMedCentralCrossRefGoogle Scholar
  134. Maisonneuve E, Gerdes K (2014) Molecular mechanisms underlying bacterial persisters. Cell 157(3):539–548. doi:10.1016/j.cell.2014.02.050PubMedCrossRefGoogle Scholar
  135. Mann PA, Muller A, Xiao L, Pereira PM, Yang C, Lee SH, Wang H, Trzeciak J, Schneeweis J, Dos Santos MM, Murgolo N, She X, Gill C, Balibar CJ, Labroli M, Su J, Flattery A, Sherborne B, Maier R, Tan CM, Black T, Onder K, Kargman S, Monsma FJ, Pinho MG, Schneider T, Roemer T (2013) Murgocil is a highly bioactive staphylococcal-specific Inhibitor of the peptidoglycan glycosyltransferase enzyme MurG. ACS Chem Biol 8:2442–2451. doi:10.1021/cb400487fPubMedCrossRefGoogle Scholar
  136. Manoil C (2013) Clarifying the role of two-component regulation in antibiotic killing. J Bacteriol 195:1857–1858. doi:10.1128/JB.00190-13PubMedPubMedCentralCrossRefGoogle Scholar
  137. Master RN, Deane J, Opiela C, Sahm DF (2013) Recent trends in resistance to cell envelope-active antibacterial agents among key bacterial pathogens. Ann N Y Acad Sci 1277:1–7. doi:10.1111/nyas.12022PubMedCrossRefGoogle Scholar
  138. Matsui T, Yamane J, Mogi N, Yamaguchi H, Takemoto H, Yao M, Tanaka I (2012) Structural reorganization of the bacterial cell-division protein FtsZ from Staphylococcus aureus. Acta Crystallogr D Biol Crystallogr 68:1175–1188. doi:10.1107/S0907444912022640PubMedCrossRefGoogle Scholar
  139. McArthur AG, Waglechner N, Nizam F, Yan A, Azad MA, Baylay AJ, Bhullar K, Canova MJ, De Pascale G, Ejim L, Kalan L, King AM, Koteva K, Morar M, Mulvey MR, O’Brien JS, Pawlowski AC, Piddock LJV, Spanogiannopoulos P, Sutherland AD, Tang I, Taylor PL, Thaker M, Wang W, Yan M, Yu T, Wright GD (2013) The comprehensive antibiotic resistance database. Antimicrob Agents Chemother 57:3348–3357. doi:10.1128/AAC. 00419-13PubMedPubMedCentralCrossRefGoogle Scholar
  140. McKenna M (2013) Antibiotic resistance: the last resort. Nature 499:394–396. doi:10.1038/499394aPubMedCrossRefGoogle Scholar
  141. Méhi O, Bogos B, Csörgo B, Päl C (2013) Genomewide screen for modulators of evolvability under toxic antibiotic exposure. Antimicrob Agents Chemother 57:3453–3456. doi:10.1128/AAC. 02454-12PubMedPubMedCentralCrossRefGoogle Scholar
  142. Mehta S, Singh C, Plata KB, Chanda PK, Paul A, Riosa S, Rosato RR, Rosato AE (2012) β-Lactams increase the antibacterial activity of daptomycin against clinical methicillin-resistant Staphylococcus aureus strains and prevent selection of daptomycin-resistant derivatives. Antimicrob Agents Chemother 56:6192–6200. doi:10.1128/AAC. 01525-12PubMedPubMedCentralCrossRefGoogle Scholar
  143. Melamed Yerushalmi S, Buck ME, Lynn DM, Lemcoff NG, Meijler MM (2013) Multivalent alteration of quorum sensing in Staphylococcus aureus. Chem Commun 49:5177–5179. doi:10.1039/c3cc41645cCrossRefGoogle Scholar
  144. Metz M, Shlaes DM (2014) Eight more ways to deal with antibiotic resistance. Antimicrob Agents Chemother 58:4253–4256. doi:10.1128/AAC. 02623-14PubMedPubMedCentralCrossRefGoogle Scholar
  145. Miskinyte M, Gordo I (2013) Increased survival of antibiotic-resistant Escherichia coli inside macrophages. Antimicrob Agents Chemother 57:189–195. doi:10.1128/AAC. 01632-12PubMedPubMedCentralCrossRefGoogle Scholar
  146. Mitsuma SF, Mansour MK, Dekker JP, Kim J, Rahman MZ, Tweed-Kent A, Schuetz P (2013) Promising new assays and technologies for the diagnosis and management of infectious diseases. Clin Infect Dis 56:996–1002. doi:10.1093/cid/cis1014PubMedCrossRefGoogle Scholar
  147. Modi SR, Lee HH, Spina CS, Collins JJ (2013) Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature 499:219–222. doi:10.1038/nature12212PubMedPubMedCentralCrossRefGoogle Scholar
  148. Montgomery JI, Brown MF, Reilly U, Price LM, Abramite JA, Arcari J, Barham R, Che Y, Chen JM, Chung SW, Collantes EM, Desbonnet C, Doroski M, Doty J, Engtrakul JJ, Harris TM, Huband M, Knafels JD, Leach KL, Liu S, Marfat A, McAllister L, McElroy E, Menard CA, Mitton-Fry M, Mullins L, Noe MC, O’Donnell J, Oliver R, Penzien J, Plummer M, Shanmugasundaram V, Thoma C, Tomaras AP, Uccello DP, Vaz A, Wishka DG (2012) Pyridone methylsulfone hydroxamate LpxC inhibitors for the treatment of serious gram-negative infections. J Med Chem 55:1662–1670. doi:10.1021/jm2014875PubMedCrossRefGoogle Scholar
  149. Moraski GC, Markley LD, Cramer J, Hipskind PA, Boshoff H, Bailey MA, Alling T, Ollinger J, Parish T, Miller MJ (2013) Advancement of imidazo[1,2-a]pyridines with improved pharmacokinetics and nM activity vs. M. tuberculosis. ACS Med Chem Lett 4:675–679. doi:10.1021/ml400088yPubMedPubMedCentralCrossRefGoogle Scholar
  150. Morkunas B, Galloway WR, Wright M, Ibbeson BM, Hodgkinson JT, O’Connell KM, Bartolucci N, Valle MD, Welch M, Spring DR (2012) Inhibition of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells by quorum sensing autoinducer-mimics. Org Biomol Chem 10:8452–8464. doi:10.1039/c2ob26501jPubMedCrossRefGoogle Scholar
  151. Morones-Ramirez JR, Winkler JA, Spina CS, Collins JJ (2013) Silver enhances antibiotic activity against gram-negative bacteria. Sci Transl Med 5:190ra81. doi:10.1126/scitranslmed.3006276Google Scholar
  152. Moya B, Beceiro A, Cabot G, Juan C, Zamorano L, Alberti S, Oliver A (2012) Pan-β-lactam resistance development in Pseudomonas aeruginosa clinical strains: molecular mechanisms, PBP profiles, and binding affinities. Antimicrob Agents Chemother 56:4771–4778. doi:10.1128/AAC. 00680-12PubMedPubMedCentralCrossRefGoogle Scholar
  153. Moynie L, Schnell R, McMahon SA, Sandalova T, Boulkerou WA, Schmidberger JW, Alphey M, Cukier C, Duthie F, Kopec J, Liu H, Jacewicz A, Hunter WN, Naismith JH, Schneider G (2013) The AEROPATH project targeting Pseudomonas aeruginosa: crystallographic studies for assessment of potential targets in early-stage drug discovery. Acta Crystallogr Sect F Struct Biol Cryst Commun 69:25–34. doi:10.1107/S1744309112044739PubMedCrossRefGoogle Scholar
  154. Munoz-Price LS, Quinn JP (2013) Deconstructing the infection control bundles for the containment of carbapenem-resistant Enterobacteriaceae. Curr Opin Infect Dis 26:378–387. doi:10.1097/01.qco.0000431853.71500.77PubMedCrossRefGoogle Scholar
  155. Nakashima R, Sakurai K, Yamasaki S, Hayashi K, Nagata C, Hoshino K, Onodera Y, Nishino K, Yamaguchi A (2013) Structural basis for the inhibition of bacterial multidrug exporters. Nature 500:102–106. doi:10.1038/nature12300PubMedCrossRefGoogle Scholar
  156. Nikitushkin VD, Demina GR, Shleeva MO, Kaprelyants AS (2013) Peptidoglycan fragments stimulate resuscitation of “non-culturable” mycobacteria. Antonie Van Leeuwenhoek 103:37–46. doi:10.1007/s10482-012-9784-1PubMedCrossRefGoogle Scholar
  157. Nonejuie P, Burkart M, Pogliano K, Pogliano J (2013) Bacterial cytological profiling rapidly identifies the cellular pathways targeted by antibacterial molecules. Proc Natl Acad Sci U S A 110:16169–16174. doi:10.1073/pnas.1311066110PubMedPubMedCentralCrossRefGoogle Scholar
  158. Novak R (2011) Are pleuromutilin antibiotics finally fit for human use? Ann NY Acad Sci 1241:71–81. doi:10.1111/j.1749-6632.2011.06219.xPubMedCrossRefGoogle Scholar
  159. O’Connell KMG, Hodgkinson JT, Sore HF, Welch M, Salmond GPC, Spring DR (2013) Combating multidrug-resistant bacteria: current strategies for the discovery of novel antibacterials. Angew Chem Int Ed 52:10706–10733. doi:10.1002/anie.201209979CrossRefGoogle Scholar
  160. O’Loughlin CT, Miller LC, Siryaporn A, Drescher K, Semmelhack MF, Bassler BL (2013) A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation. Proc Natl Acad Sci U S A 110:17981–17986. doi:10.1073/pnas.1316981110PubMedPubMedCentralCrossRefGoogle Scholar
  161. Ojima I, Kumar K, Awasthi D, Vineberg JG (2014) Drug discovery targeting cell division proteins, microtubules and FtsZ. Bioorg Med Chem 22(18):5060–5077. doi:10.1016/j.bmc.2014.02.036PubMedPubMedCentralCrossRefGoogle Scholar
  162. Ongley SE, Bian X, Zhang Y, Chau R, Gerwick WH, Müller R, Neilan BA (2013) High-titer heterologous production in E. coli of lyngbyatoxin, a PKC activator from an uncultured marine cyanobacterium. ACS Chem Biol 8:1888–1893. doi:10.1021/cb400189jPubMedCrossRefGoogle Scholar
  163. Otto M (2013a) Blocking the spread of resistance. Sci Transl Med 5:184fs17. doi:10.1126/scitranslmed.3006128.Google Scholar
  164. Otto M (2013b) Community-associated MRSA: what makes them special? Int J Med Microbiol 303:324–330. doi:10.1016/j.ijmm.2013.02.007PubMedPubMedCentralCrossRefGoogle Scholar
  165. Paphitou NI (2013) Antimicrobial resistance: action to combat the rising microbial challenges. Int J Antimicrob Agents 42(Suppl 1):S25–S28. doi:10.1016/j.ijantimicag.2013.04.007PubMedCrossRefGoogle Scholar
  166. Pasquina LW, Santa Maria JP, Walker S (2013) Teichoic acid biosynthesis as an antibiotic target. Curr Opin Microbiol 16:531–537. doi:10.1016/j.mib.2013.06.014PubMedCrossRefGoogle Scholar
  167. Paul M, Leibovici L (2013) Combination therapy for Pseudomonas aeruginosa bacteremia: where do we stand? Clin Infect Dis 57:217–220. doi:10.1093/cid/cit220PubMedCrossRefGoogle Scholar
  168. Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL (2007) Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 6:29–40. doi:10.1038/nrd2201PubMedCrossRefGoogle Scholar
  169. Peleg AY, Miyakis S, Ward DV, Earl AM, Rubio A, Cameron DR, Pillai S, Moellering RC Jr, Eliopoulos GM (2012) Whole genome characterization of the mechanisms of daptomycin resistance in clinical and laboratory derived isolates of Staphylococcus aureus. PLoS One 7:e28316. doi:10.1371/journal.pone.0028316PubMedPubMedCentralCrossRefGoogle Scholar
  170. Pelletier MR, Casella LG, Jones JW, Adams MD, Zurawski DV, Hazlett KR, Doi Y, Ernst RK (2013) Unique structural modifications are present in the lipopolysaccharide from colistin-resistant strains of Acinetobacter baumannii. Antimicrob Agents Chemother 57:4831–4840. doi:10.1128/AAC. 00865-13PubMedPubMedCentralCrossRefGoogle Scholar
  171. 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.13.12PubMedCrossRefGoogle Scholar
  172. Perry JA, Wright GD (2013) The antibiotic resistance “mobilome”: searching for the link between environment and clinic. Front Microbiol 4:138. doi:10.3389/fmicb.2013.00138PubMedPubMedCentralCrossRefGoogle Scholar
  173. Pethe K, Bifani P, Jang J, Kang S, Park S, Ahn S, Jiricek J, Jung J, Jeon HK, Cechetto J, Christophe T, Lee H, Kempf M, Jackson M, Lenaerts AJ, Pham H, Jones V, Seo MJ, Kim YM, Seo M, Seo JJ, Park D, Ko Y, Choi I, Kim R, Kim SY, Lim S, Yim SA, Nam J, Kang H, Kwon H, Oh CT, Cho Y, Jang Y, Kim J, Chua A, Tan BH, Nanjundappa MB, Rao SP, Barnes WS, Wintjens R, Walker JR, Alonso S, Lee S, Kim J, Oh S, Oh T, Nehrbass U, Han SJ, No Z, Lee J, Brodin P, Cho SN, Nam K, Kim J (2013) Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat Med 19:1157–1160. doi:10.1038/nm.3262PubMedCrossRefGoogle Scholar
  174. Pilhofer M, Jensen GJ (2013) The bacterial cytoskeleton: more than twisted filaments. Curr Opin Cell Biol 25:125–133. doi:10.1016/j.ceb.2012.10.019PubMedCrossRefGoogle Scholar
  175. Pinho MG, Kjos M, Veening JW (2013) How to get (a)round: mechanisms controlling growth and division of coccoid bacteria. Nat Rev Microbiol 11:601–614. doi:10.1038/nrmicro3088PubMedCrossRefGoogle Scholar
  176. Pogliano J, Pogliano N, Silverman JA (2012) Daptomycin-mediated reorganization of membrane architecture causes mislocalization of essential cell division proteins. J Bacteriol 194:4494–4504. doi:10.1128/JB.00011-12PubMedPubMedCentralCrossRefGoogle Scholar
  177. Pucci MJ, Bush K (2013) Investigational antimicrobial agents of 2013. Clin Microbiol Rev 26:792–821. doi:10.1128/CMR. 00033-13PubMedPubMedCentralCrossRefGoogle Scholar
  178. Ramsey DM, Amirul Islam M, Turnbull L, Davis RA, Whitchurch CB, McAlpine SR (2013) Psammaplysin F: a unique inhibitor of bacterial chromosomal partitioning. Bioorg Med Chem Lett 23:4862–4866. doi:10.1016/j.bmcl.2013.06.082PubMedCrossRefGoogle Scholar
  179. Rateb ME, Hallyburton I, Houssen WE, Bull AT, Goodfellow M, Santhanam R, Jaspars M, Ebel R (2013) Induction of diverse secondary metabolites in Aspergillus fumigatus by microbial co-culture. RSC Adv 3:14444–14450. doi:10.1039/C3RA42378FCrossRefGoogle Scholar
  180. Reimold C, Defeu Soufo HJ, Dempwolff F, Graumann PL (2013) Motion of variable-length MreB filaments at the bacterial cell membrane influences cell morphology. Mol Biol Cell 24:2340–2349. doi:10.1091/mbc.E12-10-0728PubMedPubMedCentralCrossRefGoogle Scholar
  181. Reuter S, Ellington MJ, Cartwright EJ, Koser CU, Torok ME, Gouliouris T, Harris SR, Brown NM, Holden MT, Quail M, Parkhill J, Smith GP, Bentley SD, Peacock SJ (2013) Rapid bacterial whole-genome sequencing to enhance diagnostic and public health microbiology. JAMA Intern Med 173:1397–1404. doi:10.1001/jamainternmed.2013.7734PubMedPubMedCentralCrossRefGoogle Scholar
  182. Richter SG, Elli D, Kim HK, Hendrickx APA, Sorg JA, Schneewind O, Missiakas D (2013) Small molecule inhibitor of lipoteichoic acid synthesis is an antibiotic for gram-positive bacteria. Proc Natl Acad Sci U S A 110:3531–3536. doi:10.1073/pnas.1217337110PubMedPubMedCentralCrossRefGoogle Scholar
  183. Riley MA, Robinson SM, Roy CM, Dorit RL (2013) Rethinking the composition of a rational antibiotic arsenal for the 21st century. Future Med Chem 5:1231–1242. doi:10.4155/fmc.13.79PubMedCrossRefGoogle Scholar
  184. Rodriguez-Rojas A, Rodriguez-Beltran J, Couce A, Blazquez J (2013) Antibiotics and antibiotic resistance: a bitter fight against evolution. Int J Med Microbiol 303:293–297. doi:10.1016/j.ijmm.2013.02.004PubMedCrossRefGoogle Scholar
  185. Roemer T, Boone C (2013) Systems-level antimicrobial drug and drug synergy discovery. Nat Chem Biol 9:222–231. doi:10.1038/nchembio.1205PubMedCrossRefGoogle Scholar
  186. Roemer T, Davies J, Giaever G, Nislow C (2012) Bugs, drugs and chemical genomics. Nat Chem Biol 8:46–56. doi:10.1038/nchembio.744CrossRefGoogle Scholar
  187. Roemer T, Schneider T, Pinho MG (2013) Auxiliary factors: a chink in the armor of MRSA resistance to beta-lactam antibiotics. Curr Opin Microbiol 16:538–548. doi:10.1016/j.mib.2013.06.012PubMedCrossRefGoogle Scholar
  188. Ruiz-Avila LB, Huecas S, Artola M, Vergoñós A, Ramírez-Aportela E, Cercenado E, Barasoain I, Vázquez-Villa H, Martín-Fontecha M, Chacón P, López-Rodríguez ML, Andreu JM (2013) Synthetic inhibitors of bacterial cell division targeting the GTP binding site of FtsZ. ACS Chem Biol 8:2072–2083. doi:10.1021/cb400208zPubMedCrossRefGoogle Scholar
  189. Saroj SD, Rather PN (2013) Streptomycin inhibits quorum sensing in Acinetobacter baumannii. Antimicrob Agents Chemother 57:1926–1929. doi:10.1128/AAC. 02161-12PubMedPubMedCentralCrossRefGoogle Scholar
  190. Sass P, Brötz-Oesterhelt H (2013) Bacterial cell division as a target for new antibiotics. Curr Opin Microbiol 16:522–530. doi:10.1016/j.mib.2013.07.006PubMedCrossRefGoogle Scholar
  191. Schäberle TF, Hack IM (2014) Overcoming the current deadlock in antibiotic research. Trends Microbiol 22:165–167. doi:10.1016/j.tim.2013.12.007PubMedCrossRefGoogle Scholar
  192. Schaffner-Barbero C, Martin-Fontecha M, Chacon P, Andreu JM (2012) Targeting the assembly of bacterial cell division protein FtsZ with small molecules. ACS Chem Biol 7:269–277. doi:10.1021/cb2003626PubMedCrossRefGoogle Scholar
  193. Sears P, Ichikawa Y, Ruiz N, Gorbach S (2013) Advances in the treatment of Clostridium difficile with fidaxomicin: a narrow spectrum antibiotic. Ann NY Acad Sci 1291:33–41. doi:10.1111/nyas.12135PubMedCrossRefGoogle Scholar
  194. Seger C, Sturm S, Stuppner H (2013) Mass spectrometry and NMR spectroscopy: modern high-end detectors for high resolution separation techniques–state of the art in natural product HPLC-MS, HPLC-NMR, and CE-MS hyphenations. Nat Prod Rep 30:970–987. doi:10.1039/c3np70015aPubMedCrossRefGoogle Scholar
  195. Sewell EW, Brown ED (2014) Taking aim at wall teichoic acid synthesis: new biology and new leads for antibiotics. J Antibiot (Tokyo) 67:43–51. doi:10.1038/ja.2013.100CrossRefGoogle Scholar
  196. Shapiro S (2013) Speculative strategies for new antibacterials: all roads should not lead to Rome. J Antibiot (Tokyo) 66:371–386. doi:10.1038/ja.2013.27CrossRefGoogle Scholar
  197. Sherman DJ, Okuda S, Denny WA, Kahne D (2013) Validation of inhibitors of an ABC transporter required to transport lipopolysaccharide to the cell surface in Escherichia coli. Bioorg Med Chem 21:4846–4851. doi:10.1016/j.bmc.2013.04.020PubMedCrossRefGoogle Scholar
  198. Shlaes DM (2013) New β-lactam–β-lactamase inhibitor combinations in clinical development. Ann N Y Acad Sci 1277:105–114. doi:10.1111/nyas.12010PubMedCrossRefGoogle Scholar
  199. Shlaes DM, Spellberg B (2012) Overcoming the challenges to developing new antibiotics. Curr Opin Pharmacol 12:522–526. doi:10.1016/j.coph.2012.06.010PubMedCrossRefGoogle Scholar
  200. Shlaes DM, Sahm D, Opiela C, Spellberg B (2013) The FDA reboot of antibiotic development. Antimicrob Agents Chemother 57:4605–4607. doi:10.1128/AAC. 01277-13PubMedPubMedCentralCrossRefGoogle Scholar
  201. Singh SB (2014) Confronting the challenges of discovery of novel antibacterial agents. Bioorg Med Chem Lett 24(16):3683–3689. doi:10.1016/j.bmcl.2014.06.053PubMedCrossRefGoogle Scholar
  202. Song Y, Rubio A, Jayaswal RK, Silverman JA, Wilkinson BJ (2013) Additional routes to Staphylococcus aureus daptomycin resistance as revealed by comparative genome sequencing, transcriptional profiling, and phenotypic studies. PLoS One 8:e58469. doi:10.1371/journal.pone.0058469PubMedPubMedCentralCrossRefGoogle Scholar
  203. Spellberg B, Bartlett JG, Gilbert DN (2013) The future of antibiotics and resistance. N Engl J Med 368:299–302. doi:10.1056/NEJMp1215093PubMedPubMedCentralCrossRefGoogle Scholar
  204. Srinivas N, Jetter P, Ueberbacher BJ, Werneburg M, Zerbe K, Steinmann J, Van der Meijden B, Bernardini F, Lederer A, Dias RL, Misson PE, Henze H, Zumbrunn J, Gombert FO, Obrecht D, Hunziker P, Schauer S, Ziegler U, Kach A, Eberl L, Riedel K, DeMarco SJ, Robinson JA (2010) Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa. Science 327:1010–1013. doi:10.1126/science.1182749PubMedCrossRefGoogle Scholar
  205. Stacy DM, Welsh MA, Rather PN, Blackwell HE (2012) Attenuation of quorum sensing in the pathogen Acinetobacter baumannii using non-native N-acyl homoserine lactones. ACS Chem Biol 7:1719–1728. doi:10.1021/cb300351xPubMedPubMedCentralCrossRefGoogle Scholar
  206. Stacy DM, Le Quement ST, Hansen CL, Clausen JW, Tolker-Nielsen T, Brummond JW, Givskov M, Nielsen TE, Blackwell HE (2013) Synthesis and biological evaluation of triazole-containing N-acyl homoserine lactones as quorum sensing modulators. Org Biomol Chem 11:938–954. doi:10.1039/c2ob27155aPubMedCrossRefGoogle Scholar
  207. Stanton TB (2013) A call for antibiotic alternatives research. Trends Microbiol 21:111–113. doi:10.1016/j.tim.2012.11.002PubMedCrossRefGoogle Scholar
  208. Stogios PJ, Spanogiannopoulos P, Evdokimova E, Egorova O, Shakya T, Todorovic N, Capretta A, Wright GD, Savchenko A (2013) Structure-guided optimization of protein kinase inhibitors reverses aminoglycoside antibiotic resistance. Biochem J 454:191–200. doi:10.1042/BJ20130317PubMedPubMedCentralCrossRefGoogle Scholar
  209. Stokes NR, Baker N, Bennett JM, Berry J, Collins I, Czaplewski LG, Logan A, Macdonald R, MacLeod L, Peasley H, Mitchell JP, Nayal N, Yadav A, Srivastava A, Haydon DJ (2013) An improved small-molecule inhibitor of FtsZ with superior in vitro potency, drug-like properties, and in vivo efficacy. Antimicrob Agents Chemother 57:317–325. doi:10.1128/AAC. 01580-12PubMedPubMedCentralCrossRefGoogle Scholar
  210. Sun X, Vilar S, Tatonetti NP (2013) High-throughput methods for combinatorial drug discovery. Sci Transl Med 5:205rv1. doi:10.1126/scitranslmed.3006667.Google Scholar
  211. Tan CM, Therien AG, Lu J, Lee SH, Caron A, Gill CJ, Lebeau-Jacob C, Benton-Perdomo L, Monteiro JM, Pereira PM, Elsen NL, Wu J, Deschamps K, Petcu M, Wong S, Daigneault E, Kramer S, Liang L, Maxwell E, Claveau D, Vaillancourt J, Skorey K, Tam J, Wang H, Meredith TC, Sillaots S, Wang-Jarantow L, Ramtohul Y, Langlois E, Landry F, Reid JC, Parthasarathy G, Sharma S, Baryshnikova A, Lumb KJ, Pinho MG, Soisson SM, Roemer T (2012) Restoring methicillin-resistant Staphylococcus aureus susceptibility to β-lactam antibiotics. Sci Transl Med 4:126ra35. doi:10.1126/scitranslmed.3003592.Google Scholar
  212. Tegos GP, Hamblin MR (2013) Disruptive innovations: new anti-infectives in the age of resistance. Curr Opin Pharmacol 13:673–677. doi:10.1016/j.coph.2013.08.012PubMedCrossRefGoogle Scholar
  213. Thaker MN, Wright GD (2014) Opportunities for synthetic biology in antibiotics: expanding glycopeptide chemical diversity. ACS Synth Biol. doi:10.1021/sb300092nGoogle Scholar
  214. Thaker MN, Wang W, Spanogiannopoulos P, Waglechner N, King AM, Medina R, Wright GD (2013) Identifying producers of antibacterial compounds by screening for antibiotic resistance. Nat Biotechnol 31:922–927. doi:10.1038/nbt.2685PubMedCrossRefGoogle Scholar
  215. Thorsing M, Klitgaard JK, Atilano ML, Skov MN, Kolmos HJ, Filipe SR, Kallipolitis BH (2013) Thioridazine induces major changes in global gene expression and cell wall composition in methicillin-resistant Staphylococcus aureus USA300. PLoS One 8:e64518. doi:10.1371/journal.pone.0064518PubMedPubMedCentralCrossRefGoogle Scholar
  216. Tran TT, Panesso D, Gao H, Roh JH, Munita JM, Reyes J, Diaz L, Lobos EA, Shamoo Y, Mishra NN, Bayer AS, Murray BE, Weinstock GM, Arias CA (2013) Whole-genome analysis of a daptomycin-susceptible Enterococcus faecium strain and its daptomycin-resistant variant arising during therapy. Antimicrob Agents Chemother 57:261–268. doi:10.1128/AAC. 01454-12PubMedPubMedCentralCrossRefGoogle Scholar
  217. Tremblay LW, Xu H, Blanchard JS (2010) Structures of the Michaelis complex (1.2 Å) and the covalent acyl intermediate (2.0 Å) of cefamandole bound in the active sites of the M. tuberculosis β-lactamase K73A and E166A mutants. Biochemistry 49:9685–9687. doi:10.1021/bi1015088PubMedPubMedCentralCrossRefGoogle Scholar
  218. Van Oudenhove L, De Vriendt K, Van Beeumen J, Mercuri PS, Devreese B (2012) Differential proteomic analysis of the response of Stenotrophomonas maltophilia to imipenem. Appl Microbiol Biotechnol 95:717–733. doi:10.1007/s00253-012-4167-0PubMedCrossRefGoogle Scholar
  219. Vatansever F, de Melo WC, Avci P, Vecchio D, Sadasivam M, Gupta A, Chandran R, Karimi M, Parizotto NA, Yin R, Tegos GP, Hamblin MR (2013) Antimicrobial strategies centered around reactive oxygen species – bactericidal antibiotics, photodynamic therapy, and beyond. FEMS Microbiol Rev 37:955–989. doi:10.1111/1574-6976.12026PubMedPubMedCentralCrossRefGoogle Scholar
  220. Velikova N, Bem AE, van Baarlen P, Wells JM, Marina A (2013) WalK, the path towards new antibacterials with low potential for resistance development. ACS Med Chem Lett 4:891–894. doi:10.1021/ml400320sPubMedPubMedCentralCrossRefGoogle Scholar
  221. Vignaroli C, Rinaldi C, Varaldo PE, Lee CH, Chen FJ, Lauderdale TL (2011) Striking “seesaw effect” between daptomycin nonsusceptibility and β-lactam susceptibility in Staphylococcus haemolyticus. Antimicrob Agents Chemother 55:2495–2497. doi:10.1128/AAC. 00224-11PubMedPubMedCentralCrossRefGoogle Scholar
  222. Walsh CT, Wencewicz TA (2014) Prospects for new antibiotics: a molecule-centered perspective. J Antibiot (Tokyo) 67:7–22. doi:10.1038/ja.2013.49CrossRefGoogle Scholar
  223. Walsh CT, O’Brien RV, Khosla C (2013) Nonproteinogenic amino acid building blocks for nonribosomal peptide and hybrid polyketide scaffolds. Angew Chem Int Ed 52:7098–7124. doi:10.1002/anie.201208344CrossRefGoogle Scholar
  224. Wang H, Gill CJ, Lee SH, Mann P, Zuck P, Meredith TC, Murgolo N, She X, Kales S, Liang L, Liu J, Wu J, Santa Maria J, Su J, Pan J, Hailey J, Mcguinness D, Tan CM, Flattery A, Walker S, Black T, Roemer T (2013) Discovery of wall teichoic acid inhibitors as potential anti-MRSA β-lactam combination agents. Chem Biol 20:272–284. doi:10.1016/j.chembiol.2012.11.013PubMedPubMedCentralCrossRefGoogle Scholar
  225. Wanty C, Anandan A, Piek S, Walshe J, Ganguly J, Carlson RW, Stubbs KA, Kahler CM, Vrielink A (2013) The structure of the neisserial lipooligosaccharide phosphoethanolamine transferase A (LptA) required for resistance to polymyxin. J Mol Biol 425:3389–3402. doi:10.1016/j.jmb.2013.06.029PubMedCrossRefGoogle Scholar
  226. Warmus JS, Quinn CL, Taylor C, Murphy ST, Johnson TA, Limberakis C, Ortwine D, Bronstein J, Pagano P, Knafels JD, Lightle S, Mochalkin I, Brideau R, Podoll T (2012) Structure based design of an in vivo active hydroxamic acid inhibitor of P. aeruginosa LpxC. Bioorg Med Chem Lett 22:2536–2543. doi:10.1016/j.bmcl.2012.01.140PubMedCrossRefGoogle Scholar
  227. Watkins RR, Bonomo RA (2013) Increasing prevalence of carbapenem-resistant Enterobacteriaceae and strategies to avert a looming crisis. Expert Rev Anti-Infect Ther 11:543–545. doi:10.1586/eri.13.46PubMedCrossRefGoogle Scholar
  228. Watrous J, Roach P, Alexandrov T, Heath BS, Yang JY, Kersten RD, van der Voort M, Pogliano K, Gross H, Raaijmakers JM, Moore BS, Laskin J, Bandeira N, Dorrestein PC (2012) Mass spectral molecular networking of living microbial colonies. Proc Natl Acad Sci U S A 109:E1743–E1752. doi:10.1073/pnas.1203689109PubMedPubMedCentralCrossRefGoogle Scholar
  229. Wellington EMH, Boxall ABA, Cross P, Feil EJ, Gaze WH, Hawkey PM, Johnson-Rollings AS, Jones DL, Lee NM, Otten W, Thomas CM, Williams AP (2013) The role of the natural environment in the emergence of antibiotic resistance in gram-negative bacteria. Lancet Infect Dis 13:155–165. doi:10.1016/S1473-3099(12)70317-1PubMedCrossRefGoogle Scholar
  230. Werneburg M, Zerbe K, Juhas M, Bigler L, Stalder U, Kaech A, Ziegler U, Obrecht D, Eberl L, Robinson JA (2012) Inhibition of lipopolysaccharide transport to the outer membrane in Pseudomonas aeruginosa by peptidomimetic antibiotics. ChemBioChem 13:1767–1775. doi:10.1002/cbic.201200276PubMedCrossRefGoogle Scholar
  231. Werth BJ, Steed ME, Kaatz GW, Rybak MJ (2013a) Evaluation of ceftaroline activity against heteroresistant vancomycin-intermediate Staphylococcus aureus and vancomycin-intermediate methicillin-resistant S. aureus strains in an in vitro pharmacokinetic/pharmacodynamic model: exploring the ‘Seesaw Effect’. Antimicrob Agents Chemother 57:2664–2668. doi:10.1128/AAC. 02308-12PubMedPubMedCentralCrossRefGoogle Scholar
  232. Werth BJ, Vidaillac C, Murray KP, Newton KL, Sakoulas G, Nonejuie P, Pogliano J, Rybak MJ (2013b) Novel combinations of vancomycin plus ceftaroline or oxacillin against methicillin-resistant vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA. Antimicrob Agents Chemother 57:2376–2379. doi:10.1128/AAC. 02354-12PubMedPubMedCentralCrossRefGoogle Scholar
  233. Wilke KE, Carlson EE (2013) All signals lost. Sci Transl Med 5:203ps12. doi:10.1126/scitranslmed.3006670.Google Scholar
  234. Wilson MZ, Gitai Z (2013) Beyond the cytoskeleton: mesoscale assemblies and their function in spatial organization. Curr Opin Microbiol 16:177–183. doi:10.1016/j.mib.2013.03.008PubMedPubMedCentralCrossRefGoogle Scholar
  235. Wilson MC, Piel J (2013) Metagenomic approaches for exploiting uncultivated bacteria as a resource for novel biosynthetic enzymology. Chem Biol 20:636–647. doi:10.1016/j.chembiol.2013.04.011PubMedCrossRefGoogle Scholar
  236. Winstel V, Liang C, Sanchez-Carballo P, Steglich M, Munar M, Bröker BM, Penadés JR, Nübel U, Holst O, Dandekar T, Peschel A, Xia G (2013) Wall teichoic acid structure governs horizontal gene transfer between major bacterial pathogens. Nat Commun 4:2345. doi:10.1038/ncomms3345PubMedPubMedCentralCrossRefGoogle Scholar
  237. Worthington RJ, Melander C (2013a) Combination approaches to combat multidrug-resistant bacteria. Trends Biotechnol 31:177–184. doi:10.1016/j.tibtech.2012.12.006PubMedPubMedCentralCrossRefGoogle Scholar
  238. Worthington RJ, Melander C (2013b) Overcoming resistance to β-lactam antibiotics. J Org Chem 78:4207–4213. doi:10.1021/jo400236fPubMedPubMedCentralCrossRefGoogle Scholar
  239. Worthington RJ, Blackledge MS, Melander C (2013) Small-molecule inhibition of bacterial two-component systems to combat antibiotic resistance and virulence. Future Med Chem 5:1265–1284. doi:10.4155/fmc.13.58PubMedCrossRefGoogle Scholar
  240. Wright G (2014) Perspective: synthetic biology revives antibiotics. Nature 509:S13. doi:10.1038/509S13aPubMedCrossRefGoogle Scholar
  241. 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.201310843CrossRefGoogle Scholar
  242. Xiao XY, Hunt DK, Zhou J, Clark RB, Dunwoody N, Fyfe C, Grossman TH, O’Brien WJ, Plamondon L, Ronn M, Sun C, Zhang WY, Sutcliffe JA (2012) Fluorocyclines. 1. 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: a potent, broad spectrum antibacterial agent. J Med Chem 55:597–605. doi:10.1021/jm201465wPubMedCrossRefGoogle Scholar
  243. Yan J, Wang K, Dang W, Chen R, Xie J, Zhang B, Song J, Wang R (2013) Two hits are better than one: Membrane-active and DNA binding-related double-action mechanism of NK-18, a novel antimicrobial peptide derived from mammalian NK-Lysin. Antimicrob Agents Chemother 57:220–228. doi:10.1128/AAC. 01619-12PubMedPubMedCentralCrossRefGoogle Scholar
  244. Yun M-K, Wu Y, Li Z, Zhao Y, Waddell MB, Ferreira AM, Lee RE, Bashford D, White SW (2012) Catalysis and sulfa drug resistance in dihydropteroate synthase. Science 335:1110–1114. doi:10.1126/science.1214641PubMedPubMedCentralCrossRefGoogle Scholar
  245. Zakeri B, Lu TK (2013) Synthetic biology of antimicrobial discovery. ACS Synth Biol 2:358–372. doi:10.1021/sb300101gPubMedCrossRefGoogle Scholar
  246. Zaknoon F, Goldberg K, Sarig H, Epand RF, Epand RM, Mor A (2012) Antibacterial properties of an oligo-acyl-lysyl hexamer targeting gram-negative species. Antimicrob Agents Chemother 56:4827–4832. doi:10.1128/AAC.00511-12PubMedPubMedCentralCrossRefGoogle Scholar
  247. 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.2013.09.007PubMedPubMedCentralCrossRefGoogle Scholar
  248. Zhu J, Kaufmann GF (2013) Quo vadis quorum quenching? Curr Opin Pharmacol 13:688–698. doi:10.1016/j.coph.2013.07.003PubMedCrossRefGoogle Scholar
  249. Zlitni S, Ferruccio LF, Brown ED (2013) Metabolic suppression identifies new antibacterial inhibitors under nutrient limitation. Nat Chem Biol 9:796–804. doi:10.1038/nchembio.1361PubMedPubMedCentralCrossRefGoogle Scholar
  250. Zoraghi R, Reiner NE (2013) Protein interaction networks as starting points to identify novel antimicrobial drug targets. Curr Opin Microbiol 16:566–572. doi:10.1016/j.mib.2013.07.010PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Jed F. Fisher
    • 1
    Email author
  • Jarrod W. Johnson
    • 1
  • Shahriar Mobashery
    • 1
  1. 1.Department of Chemistry and BiochemistryUniversity of Notre DameNotre Dame, INUSA

Personalised recommendations