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Antibiotic Adjuvants

Chapter
Part of the Topics in Medicinal Chemistry book series

Abstract

Bacteria are becoming increasingly resistant to currently available antibiotics, and the development of new antibiotics is not keeping pace. Alternative approaches to combatting drug-resistant bacteria are sorely needed. One such approach is the development of small-molecule antibiotic adjuvants. Adjuvants that thwart resistance mechanisms and render bacteria susceptible to antibiotics have the potential to prolong the life span and also to extend the spectrum of our current armamentarium of drugs. Several approaches to the development of potential adjuvant therapeutics have been investigated, based upon combatting various resistance mechanisms, and have identified promising adjuvant classes. These classes include adjuvants that inhibit modification or degradation of the antibiotic by enzymes (such as β-lactamases or the aminoglycoside-modifying enzymes), adjuvants that increase the intracellular concentration of the antibiotic by inhibiting efflux or facilitating antibiotic uptake, adjuvants that interfere with bacterial signaling systems that drive or coordinate resistance mechanisms, and finally adjuvants that target nonessential steps in bacterial cell wall synthesis. The antibiotic adjuvant approach is a promising orthogonal strategy for the development of new antibiotics to combat drug-resistant bacteria.

Keywords

Adjuvant Antibiotic-modifying enzymes Antibiotics Efflux Multidrug-resistant bacteria 

References

  1. 1.
    Wright GD (2016) Antibiotic adjuvants: rescuing antibiotics from resistance. Trends Microbiol 24:862–871. doi: 10.1016/j.tim.2016.06.009 PubMedCrossRefGoogle Scholar
  2. 2.
    Dolgin E (2010) Sequencing of superbugs seen as key to combating their spread. Nat Med 16:1054–1054. doi: 10.1038/Nm1010-1054a Google Scholar
  3. 3.
    Lewis II JS, Owens A, Cadena J, Sabol K, Patterson JE, Jorgensen JH (2005) Emergence of daptomycin resistance in Enterococcus faecium during daptomycin therapy. Antimicrob Agents Chemother 49:1664–1665. doi: 10.1128/AAC.49.4.1664-1665.2005 PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Gonzales RD, Schreckenberger PC, Graham MB, Kelkar S, DenBesten K, Quinn JP (2001) Infections due to vancomycin-resistant Enterococcus faecium resistant to linezolid. Lancet 357:1179. doi: 10.1016/S0140-6736(00)04376-2 PubMedCrossRefGoogle Scholar
  5. 5.
    Pawlowski AC, Johnson JW, Wright GD (2016) Evolving medicinal chemistry strategies in antibiotic discovery. Curr Opin Biotechnol 42:108–117. doi: 10.1016/j.copbio.2016.04.006 PubMedCrossRefGoogle Scholar
  6. 6.
    Gill EE, Franco OL, Hancock REW (2015) Antibiotic adjuvants: diverse strategies for controlling drug-resistant pathogens. Chem Biol Drug Des 85:56–78. doi: 10.1111/cbdd.12478 PubMedCrossRefGoogle Scholar
  7. 7.
    Roemer T, Boone C (2013) Systems-level antimicrobial drug and drug synergy discovery. Nat Chem Biol 9:222–231. doi: 10.1038/nchembio.1205 PubMedCrossRefGoogle Scholar
  8. 8.
    Rodriguez de Evgrafov M, Gumpert H, Munck C, Thomsen TT, Sommer MO (2015) Collateral resistance and sensitivity modulate evolution of high-level resistance to drug combination treatment in Staphylococcus aureus. Mol Biol Evol 32:1175–1185. doi: 10.1093/molbev/msv006 PubMedCrossRefGoogle Scholar
  9. 9.
    Walsh C (2000) Molecular mechanisms that confer antibacterial drug resistance. Nature 406:775–781. doi: 10.1038/35021219 PubMedCrossRefGoogle Scholar
  10. 10.
    Wright GD (2005) Bacterial resistance to antibiotics: enzymatic degradation and modification. Adv Drug Delivery Rev 57:1451–1470. doi: 10.1016/j.addr.2005.04.002 CrossRefGoogle Scholar
  11. 11.
    Ramirez MS, Tolmasky ME (2010) Aminoglycoside modifying enzymes. Drug Resist Updates 13:151–171. doi: 10.1016/j.drup.2010.08.003 CrossRefGoogle Scholar
  12. 12.
    Volkers G, Palm GJ, Weiss MS, Wright GD, Hinrichs W (2011) Structural basis for a new tetracycline resistance mechanism relying on the TetX monooxygenase. FEBS Lett 585:1061–1066. doi: 10.1016/j.febslet.2011.03.012 PubMedCrossRefGoogle Scholar
  13. 13.
    Jovetic S, Zhu Y, Marcone GL, Marinelli F, Tramper J (2010) β-Lactam and glycopeptide antibiotics: first and last line of defense? Trends Biotechnol 28:596–604. doi: 10.1016/j.tibtech.2010.09.004 PubMedCrossRefGoogle Scholar
  14. 14.
    Drawz SM, Papp-Wallace KM, Bonomo RA (2014) New β-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob Agents Chemother 58:1835–1846. doi: 10.1128/AAC.00826-13 PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Papp-Wallace KM, Bonomo RA (2016) New β-lactamase inhibitors in the clinic. Infect Dis Clin North Am 30:441–464. doi: 10.1016/j.idc.2016.02.007 PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Drawz SM, Bonomo RA (2010) Three decades of β-lactamase inhibitors. Clin Microbiol Rev 23:160–201. doi: 10.1128/CMR.00037-09 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Bush K (2015) A resurgence of β-lactamase inhibitor combinations effective against multidrug-resistant Gram-negative pathogens. Int J Antimicrob Agents 46:483–493. doi: 10.1016/j.ijantimicag.2015.08.011 PubMedCrossRefGoogle Scholar
  18. 18.
    Ball P (2007) The clinical development and launch of amoxicillin/clavulanate for the treatment of a range of community-acquired infections. Int J Antimicrob Agents 30(Suppl 2):S113–S117. doi: 10.1016/j.ijantimicag.2007.07.037 PubMedCrossRefGoogle Scholar
  19. 19.
    Walsh C (2003) Where will new antibiotics come from? Nat Rev Microbiol 1:65–70. doi: 10.1038/nrmicro727 PubMedCrossRefGoogle Scholar
  20. 20.
    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.12010 ADSPubMedCrossRefGoogle Scholar
  21. 21.
    Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Kern G, Walkup GK, Fisher SL (2012) Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor. Proc Natl Acad Sci U S A 109(29):11663–11668. doi: 10.1073/pnas.1205073109 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Levasseur P, Girard AM, Miossec C, Pace J, Coleman K (2015) In vitro antibacterial activity of the ceftazidime-avibactam combination against Enterobacteriaceae, including strains with well-characterized β-lactamases. Antimicrob Agents Chemother 59:1931–1934. doi: 10.1128/AAC.04218-14 PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Klibanov OM, Phan D, Ferguson K (2015) Drug updates and approvals: 2015 in review. Nurse Pract 40:34–43. doi: 10.1097/01.NPR.0000473071.26873.3c PubMedCrossRefGoogle Scholar
  24. 24.
    Petersen PJ, Jones CH, Venkatesan AM, Bradford PA (2009) Efficacy of piperacillin combined with the penem β-lactamase inhibitor BLI-489 in murine models of systemic infection. Antimicrob Agents Chemother 53:1698–1700. doi: 10.1128/AAC.01549-08 PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Bassetti M, Ginocchio F, Mikulska M (2011) New treatment options against Gram-negative organisms. Crit Care 15:215. doi: 10.1186/cc9997 PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Paukner S, Hesse L, Prezelj A, Solmajer T, Urleb U (2009) In vitro activity of LK-157, a novel tricyclic carbapenem as broad-spectrum β-lactamase inhibitor. Antimicrob Agents Chemother 53:505–511. doi: 10.1128/AAC.00085-08 PubMedCrossRefGoogle Scholar
  27. 27.
    Livermore DM, Mushtaq S (2013) Activity of biapenem (RPX2003) combined with the boronate β-lactamase inhibitor RPX7009 against carbapenem-resistant Enterobacteriaceae. J Antimicrob Chemother 68:1825–1831. doi: 10.1093/jac/dkt118 PubMedCrossRefGoogle Scholar
  28. 28.
    Lapuebla A, Abdallah M, Olafisoye O, Cortes C, Urban C, Quale J, Landman D (2015) Activity of meropenem combined with RPX7009, a novel β-lactamase inhibitor, against Gram-negative clinical isolates in New York City. Antimicrob Agents Chemother 59:4856–4860. doi: 10.1128/AAC.00843-15 PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Griffith DC, Loutit JS, Morgan EE, Durso S, Dudley MN (2016) Phase 1 study of the safety, tolerability, and pharmacokinetics of the β-lactamase inhibitor vaborbactam (RPX7009) in healthy adult subjects. Antimicrob Agents Chemother 60:6326–6332. doi: 10.1128/AAC.00568-16 PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    van Duin D, Bonomo RA (2016) Ceftazidime/avibactam and ceftolozane/tazobactam: second-generation β-lactam/β-lactamase inhibitor combinations. Clin Infect Dis 63:234–241. doi: 10.1093/cid/ciw243 PubMedCrossRefGoogle Scholar
  31. 31.
    Walsh TR, Toleman MA, Poirel L, Nordmann P (2005) Metallo-β-lactamases: the quiet before the storm? Clin Microbiol Rev 18:306–325. doi: 10.1128/CMR.18.2.306-325.2005 PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    King AM, Reid-Yu SA, Wang W, King DT, De Pascale G, Strynadka NC, Walsh TR, Coombes BK, Wright GD (2014) Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance. Nature 510:503–506. doi: 10.1038/nature13445 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Cornaglia G, Giamarellou H, Rossolini GM (2011) Metallo-β-lactamases: a last frontier for β-lactams? Lancet Infect Dis 11(5):381–393. doi: 10.1016/S1473-3099(11)70056-1 PubMedCrossRefGoogle Scholar
  34. 34.
    Nordmann P, Poirel L, Walsh TR, Livermore DM (2011) The emerging NDM carbapenemases. Trends Microbiol 19:588–595. doi: 10.1016/j.tim.2011.09.005 PubMedCrossRefGoogle Scholar
  35. 35.
    Page MGP, Dantier C, Desarbre E, Gaucher B, Gebhardt K, Schmitt-Hoffmann A (2011) In vitro and in vivo properties of BAL30376, a β-lactam and dual β-lactamase inhibitor combination with enhanced activity against Gram-negative bacilli that express multiple β-lactamases. Antimicrob Agents Chemother 55:1510–1519. doi: 10.1128/AAC.01370-10 PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Hinchliffe P, Gonzalez MM, Mojica MF, Gonzalez JM, Castillo V, Saiz C, Kosmopoulou M, Tooke CL, Llarrull LI, Mahler G, Bonomo RA, Vila AJ, Spencer J (2016) Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes. Proc Natl Acad Sci U S A 113:E3745–E3754. doi: 10.1073/pnas.1601368113 PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Labby KJ, Garneau-Tsodikova S (2013) Strategies to overcome the action of aminoglycoside-modifying enzymes for treating resistant bacterial infections. Future Med Chem 5(11):1285–1309. doi: 10.4155/fmc.13.80 PubMedCrossRefGoogle Scholar
  38. 38.
    Gao F, Yan X, Shakya T, Baettig OM, Ait-Mohand-Brunet S, Berghuis AM, Wright GD, Auclair K (2006) Synthesis and SAR of truncated bisubstrate inhibitors of aminoglycoside 6'-N-acetyltransferases. J Med Chem 49:5273–5281. doi: 10.1021/jm060732n PubMedCrossRefGoogle Scholar
  39. 39.
    Lin DL, Tran T, Alam JY, Herron SR, Ramirez MS, Tolmasky ME (2014) Inhibition of aminoglycoside 6'-N-acetyltransferase type Ib by zinc: reversal of amikacin resistance in Acinetobacter baumannii and Escherichia coli by a zinc ionophore. Antimicrob Agents Chemother 58:4238–4241. doi: 10.1128/Aac.00129-14 PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Li Y, Green KD, Johnson BR, Garneau-Tsodikova S (2015) Inhibition of aminoglycoside acetyltransferase resistance enzymes by metal salts. Antimicrob Agents Chemother 59:4148–4156. doi: 10.1128/AAC.00885-15 PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Chiem K, Fuentes BA, Lin DL, Tran T, Jackson A, Ramirez MS, Tolmasky ME (2015) Inhibition of aminoglycoside 6'-N-acetyltransferase Type Ib-mediated amikacin resistance in Klebsiella pneumoniae by zinc and copper pyrithione. Antimicrob Agents Chemother 59:5851–5853. doi: 10.1128/Aac.01106-15 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Shakya T, Stogios PJ, Waglechner N, Evdokimova E, Ejim L, Blanchard JE, McArthur AG, Savchenko A, Wright GD (2011) A small molecule discrimination map of the antibiotic resistance kinome. Chem Biol 18:1591–1601. doi: 10.1016/j.chembiol.2011.10.018 PubMedCrossRefGoogle Scholar
  43. 43.
    Suga T, Ishii T, Iwatsuki M, Yamamoto T, Nonaka K, Masuma R, Matsui H, Hanaki H, Omura S, Shiomi K (2012) Aranorosin circumvents arbekacin-resistance in MRSA by inhibiting the bifunctional enzyme AAC(6′)/APH(2″). J Antibiot 65:527–529. doi: 10.1038/ja.2012.53 PubMedCrossRefGoogle Scholar
  44. 44.
    Hernick M (2013) Mycothiol: a target for potentiation of rifampin and other antibiotics against Mycobacterium tuberculosis. Expert Rev Anti-Infect Ther 11:49–67. doi: 10.1586/Eri.12.152 PubMedCrossRefGoogle Scholar
  45. 45.
    Gutierrez-Lugo MT, Baker H, Shiloach J, Boshoff H, Bewley CA (2009) Dequalinium, a new inhibitor of Mycobacterium tuberculosis mycothiol ligase identified by high-throughput screening. J Biomol Screen 14:643–652. doi: 10.1177/1087057109335743 PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Ramon-Garcia S, Ng C, Anderson H, Chao JD, Zheng XJ, Pfeifer T, Av-Gay Y, Roberge M, Thompson CJ (2011) Synergistic drug combinations for tuberculosis therapy identified by a novel high-throughput screen. Antimicrob Agents Chemother 55:3861–3869. doi: 10.1128/Aac.00474-11 PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Pieren M, Tigges M (2012) Adjuvant strategies for potentiation of antibiotics to overcome antimicrobial resistance. Curr Opin Pharmacol 12:551–555. doi: 10.1016/j.coph.2012.07.005 PubMedCrossRefGoogle Scholar
  48. 48.
    Maravic G (2004) Macrolide resistance based on the Erm-mediated rRNA methylation. Curr Drug Targets Infect Disord 4:193–202. doi: 10.2174/1568005043340777 PubMedCrossRefGoogle Scholar
  49. 49.
    Clancy J, Schmieder BJ, Petitpas JW, Manousos M, Williams JA, Faiella JA, Girard AE, McGuirk PR (1995) Assays to detect and characterize synthetic agents that inhibit the ErmC methyltransferase. J Antibiot (Tokyo) 48:1273–1279. doi: 10.7164/antibiotics.48.1273 CrossRefGoogle Scholar
  50. 50.
    Feder M, Purta E, Koscinski L, Cubrilo S, Maravic Vlahovicek G, Bujnicki JM (2008) Virtual screening and experimental verification to identify potential inhibitors of the ErmC methyltransferase responsible for bacterial resistance against macrolide antibiotics. ChemMedChem 3:316–322. doi: 10.1002/cmdc.200700201 PubMedCrossRefGoogle Scholar
  51. 51.
    Webber MA, Piddock LJV (2003) The importance of efflux pumps in bacterial antibiotic resistance. J Antimicrob Chemother 51:9–11. doi: 10.1093/jac/dkg050 PubMedCrossRefGoogle Scholar
  52. 52.
    Li XZ, Plesiat P, Nikaido H (2015) The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev 28:337–418. doi: 10.1128/CMR.00117-14 PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Jang S (2016) Multidrug efflux pumps in Staphylococcus aureus and their clinical implications. J Microbiol 54:1–8. doi: 10.1007/s12275-016-5159-z PubMedCrossRefGoogle Scholar
  54. 54.
    Abreu AC, McBain AJ, Simoes M (2012) Plants as sources of new antimicrobials and resistance-modifying agents. Nat Prod Rep 29:1007–1021. doi: 10.1039/c2np20035j PubMedCrossRefGoogle Scholar
  55. 55.
    Markham PN, Westhaus E, Klyachko K, Johnson ME, Neyfakh AA (1999) Multiple novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus. Antimicrob Agents Chemother 43:2404–2408PubMedPubMedCentralGoogle Scholar
  56. 56.
    Markham PN, Neyfakh AA (1996) Inhibition of the multidrug transporter NorA prevents emergence of norfloxacin resistance in Staphylococcus aureus. Antimicrob Agents Chemother 40:2673–2674PubMedPubMedCentralGoogle Scholar
  57. 57.
    Fujita M, Shiota S, Kuroda T, Hatano T, Yoshida T, Mizushima T, Tsuchiya T (2005) Remarkable synergies between baicalein and tetracycline, and baicalein and β-lactams against methicillin-resistant Staphylococcus aureus. Microbiol Immunol 49:391–396PubMedCrossRefGoogle Scholar
  58. 58.
    Kalle AM, Rizvi A (2011) Inhibition of bacterial multidrug resistance by celecoxib, a cyclooxygenase-2 inhibitor. Antimicrob Agents Chemother 55:439–442. doi: 10.1128/AAC.00735-10 PubMedCrossRefGoogle Scholar
  59. 59.
    Sabatini S, Gosetto F, Serritella S, Manfroni G, Tabarrini O, Iraci N, Brincat JP, Carosati E, Villarini M, Kaatz GW, Cecchetti V (2012) Pyrazolo[4,3-c][1,2]benzothiazines-5,5-dioxide: a promising new class of Staphylococcus aureus NorA efflux pump inhibitors. J Med Chem 55:3568–3572. doi: 10.1021/jm201446h PubMedCrossRefGoogle Scholar
  60. 60.
    Lepri S, Buonerba F, Goracci L, Velilla I, Ruzziconi R, Schindler BD, Seo SM, Kaatz GW, Cruciani G (2016) Indole-based weapons to fight antibiotic resistance: a SAR study. J Med Chem 59:867–891. doi: 10.1021/acs.jmedchem.5b01219 PubMedCrossRefGoogle Scholar
  61. 61.
    Kaatz GW, Moudgal VV, Seo SM, Kristiansen JE (2003) Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus. Antimicrob Agents Chmother 47:719–726. doi: 10.1128/Aac.47.2.719-726.2003 CrossRefGoogle Scholar
  62. 62.
    Mirza ZM, Kumar A, Kalia NP, Zargar A, Khan IA (2011) Piperine as an inhibitor of the MdeA efflux pump of Staphylococcus aureus. J Med Microbiol 60:1472–1478. doi: 10.1099/jmm.0.033167-0 PubMedCrossRefGoogle Scholar
  63. 63.
    Lomovskaya O, Warren MS, Lee A, Galazzo J, Fronko R, Lee M, Blais J, Cho D, Chamberland S, Renau T, Leger R, Hecker S, Watkins W, Hoshino K, Ishida H, Lee VJ (2001) Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrob Agents Chemother 45:105–116. doi: 10.1128/AAC.45.1.105-116.2001 PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Pages JM, Amaral L (2009) Mechanisms of drug efflux and strategies to combat them: challenging the efflux pump of Gram-negative bacteria. Biochim Biophys Acta 1794:826–833. doi: 10.1016/j.bbapap.2008.12.011 PubMedCrossRefGoogle Scholar
  65. 65.
    Lomovskaya O, Bostian KA (2006) Practical applications and feasibility of efflux pump inhibitors in the clinic – a vision for applied use. Biochem Pharmacol 71:910–918. doi: 10.1016/j.bcp.2005.12.008 PubMedCrossRefGoogle Scholar
  66. 66.
    Chalhoub H, Saenz Y, Rodriguez-Villalobos H, Denis O, Kahl BC, Tulkens PM, Van Bambeke F (2016) High-level resistance to meropenem in clinical isolates of Pseudomonas aeruginosa in the absence of carbapenemases: role of active efflux and porin alterations. Int J Antimicrob Agents 48:740–743. doi: 10.1016/j.ijantimicag.2016.09.012 PubMedCrossRefGoogle Scholar
  67. 67.
    Bohnert JA, Schuster S, Kern WV, Karcz T, Olejarz A, Kaczor A, Handzlik J, Kiec-Kononowicz K (2016) Novel piperazine arylideneimidazolones inhibit the AcrAB-TolC pump in Escherichia coli and simultaneously act as fluorescent membrane probes in a combined real-time influx and efflux assay. Antimicrob Agents Chemother 60:1974–1983. doi: 10.1128/Aac.01995-15 PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Lawler AJ, Ricci V, Busby SJW, Piddock LJV (2013) Genetic inactivation of acrAB or inhibition of efflux induces expression of ramA. J Antimicrob Chemother 68:1551–1557. doi: 10.1093/jac/dkt069 PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Bailey AM, Paulsen IT, Piddock LJV (2008) RamA confers multidrug resistance in Salmonella enterica via increased expression of acrB, which is inhibited by chlorpromazine. Antimicrob Agents Chemother 52:3604–3611. doi: 10.1128/AAC.00661-08 PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Kinana AD, Vargiu AV, May T, Nikaido H (2016) Aminoacyl β-naphthylamides as substrates and modulators of AcrB multidrug efflux pump. Proc Natl Acad Sci U S A 113:1405–1410. doi: 10.1073/pnas.1525143113 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Saw HT, Webber MA, Mushtaq S, Woodford N, Piddock LJV (2016) Inactivation or inhibition of AcrAB-TolC increases resistance of carbapenemase-producing Enterobacteriaceae to carbapenems. J Antimicrob Chemother 71:1510–1519. doi: 10.1093/jac/dkw028 PubMedCrossRefGoogle Scholar
  72. 72.
    Piddock LJV, Garvey MI, Rahman MM, Gibbons S (2010) Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in Gram-negative bacteria. J Antimicrob Chemother 65:1215–1223. doi: 10.1093/jac/dkq079 PubMedCrossRefGoogle Scholar
  73. 73.
    Handzlik J, Szymanska E, Chevalier J, Otrgbska E, Kiec-Kononowicz K, Pages JM, Alibert S (2011) Amine-alkyl derivatives of hydantoin: new tool to combat resistant bacteria. Eur J Med Chem 46:5807–5816. doi: 10.1016/j.ejmech.2011.09.032 PubMedCrossRefGoogle Scholar
  74. 74.
    Otrebska-Machaj E, Chevalier J, Handzlik J, Szymanska E, Schabikowski J, Boyer G, Bolla JM, Kiec-Kononowicz K, Pages JM, Alibert S (2016) Efflux pump blockers in Gram-negative bacteria: the new generation of hydantoin based-modulators to improve antibiotic activity. Front Microbiol 7:622. doi: 10.3389/fmicb.2016.00622 CrossRefGoogle Scholar
  75. 75.
    Cox G, Koteva K, Wright GD (2014) An unusual class of anthracyclines potentiate Gram-positive antibiotics in intrinsically resistant Gram-negative bacteria. J Antimicrob Chemother 69:1844–1855. doi: 10.1093/jac/dku057 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Taylor PL, Rossi L, De Pascale G, Wright GD (2012) A forward chemical screen identifies antibiotic adjuvants in Escherichia coli. ACS Chem Biol 7:1547–1555. doi: 10.1021/cb300269g PubMedCrossRefGoogle Scholar
  77. 77.
    Mollmann U, Heinisch L, Bauernfeind A, Kohler T, Ankel-Fuchs D (2009) Siderophores as drug delivery agents: application of the “Trojan Horse” strategy. Biometals 22:615–624. doi: 10.1007/s10534-009-9219-2 PubMedCrossRefGoogle Scholar
  78. 78.
    Livermore DM (1990) Antibiotic uptake and transport by bacteria. Scand J Infect Dis Suppl 74:15–22. doi: 10.3109/inf.1990.22.suppl-74.01 PubMedGoogle Scholar
  79. 79.
    Lambert PA (2002) Cellular impermeability and uptake of biocides and antibiotics in Gram-positive bacteria and mycobacteria. J Appl Microbiol 92(Suppl):46S–54S. doi: 10.1046/j.1365-2672.92.5s1.7.x PubMedCrossRefGoogle Scholar
  80. 80.
    Zabawa TP, Pucci MJ, Parr Jr TR, Lister T (2016) Treatment of Gram-negative bacterial infections by potentiation of antibiotics. Curr Opin Microbiol 33:7–12. doi: 10.1016/j.mib.2016.05.005 PubMedCrossRefGoogle Scholar
  81. 81.
    Viljanen P, Vaara M (1984) Susceptibility of Gram-negative bacteria to polymyxin-B nonapeptide. Antimicrob Agents Chemother 25:701–705. doi: 10.1128/AAC.25.6.701 PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Ofek I, Cohen S, Rahmani R, Kabha K, Tamarkin D, Herzig Y, Rubinstein E (1994) Antibacterial synergism of polymyxin-B nonapeptide and hydrophobic antibiotics in experimental Gram-negative infections in mice. Antimicrob Agents Chemother 38:374–377. doi: 10.1128/AAC.38.2.374 PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Pages JM, Peslier S, Keating TA, Lavigne JP, Nichols WW (2016) Role of the outer membrane and porins in susceptibility of β-lactamase-producing Enterobacteriaceae to ceftazidime-avibactam. Antimicrob Agents Chemother 60:1349–1359. doi: 10.1128/Aac.01585-15 PubMedCentralCrossRefGoogle Scholar
  84. 84.
    Ejim L, Farha MA, Falconer SB, Wildenhain J, Coombes BK, Tyers M, Brown ED, Wright GD (2011) Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat Chem Biol 7:348–350. doi: 10.1038/nchembio.559 PubMedCrossRefGoogle Scholar
  85. 85.
    Lamers RP, Cavallari JF, Burrows LL (2013) The efflux inhibitor phenylalanine-arginine β-naphthylamide (PAβN) permeabilizes the outer membrane of Gram-negative bacteria. PLoS One 8:e60666. doi: 10.1371/journal.pone.0060666 ADSPubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Hider RC, Kong X (2010) Chemistry and biology of siderophores. Nat Prod Rep 27(5):637–657. doi: 10.1039/b906679a PubMedCrossRefGoogle Scholar
  87. 87.
    Boudreau MA, Fishovitz J, Llarrull LI, Xiao QB, Mobashery S (2015) Phosphorylation of BlaR1 in manifestation of antibiotic resistance in methicillin-resistant Staphylococcus aureus and its abrogation by small molecules. ACS Infect Dis 1(10):454–459. doi: 10.1021/acsinfecdis.5b00086 PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Gotoh Y, Eguchi Y, Watanabe T, Okamoto S, Doi A, Utsumi R (2010) Two-component signal transduction as potential drug targets in pathogenic bacteria. Curr Opin Microbiol 13:232–239. doi: 10.1016/J.Mib.2010.01.008 PubMedCrossRefGoogle Scholar
  89. 89.
    Mejean V (2016) Two-component regulatory systems: the moment of truth. Res Microbiol 167(1):1–3. doi: 10.1016/j.resmic.2015.09.004 PubMedCrossRefGoogle Scholar
  90. 90.
    Gardete S, Wu SW, Gill S, Tomasz A (2006) Role of VraSR in antibiotic resistance and antibiotic-induced stress response in Staphylococcus aureus. Antimicrob Agents Chemother 50:3424–3434. doi: 10.1128/Aac.00356-06 PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    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.13.58 PubMedCrossRefGoogle Scholar
  92. 92.
    Boyle-Vavra S, Yin SH, Jo DS, Montgomery CP, Daum RS (2013) VraT/YvqF is required for methicillin resistance and activation of the VraSR regulon in Staphylococcus aureus. Antimicrob Agents Chemother 57:83–95. doi: 10.1128/Aac.01651-12 PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Belcheva A, Golemi-Kotra D (2008) A close-up view of the VraSR two-component system. A mediator of Staphylococcus aureus response to cell wall damage. J Biol Chem 283:12354–12364. doi: 10.1074/jbc.M710010200 PubMedCrossRefGoogle Scholar
  94. 94.
    Jo DS, Montgomery CP, Yin S, Boyle-Vavra S, Daum RS (2011) Improved oxacillin treatment outcomes in experimental skin and lung infection by a methicillin-resistant Staphylococcus aureus isolate with a vraSR operon deletion. Antimicrob Agents Chemother 55:2818–2823. doi: 10.1128/AAC.01704-10 PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Matsuo M, Kato F, Oogai Y, Kawai T, Sugai M, Komatsuzawa H (2010) Distinct two-component systems in methicillin-resistant Staphylococcus aureus can change the susceptibility to antimicrobial agents. J Antimicrob Chemother 65:1536–1537. doi: 10.1093/jac/dkq141 PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Rogers SA, Huigens RW, Cavanagh J, Melander C (2010) Synergistic effects between conventional antibiotics and 2-aminoimidazole-derived antibiofilm agents. Antimicrob Agents Chemother 54:2112–2118. doi: 10.1128/AAC.01418-09 PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Su Z, Peng L, Worthington RJ, Melander C Evaluation of 4,5-disubstituted-2-aminoimidazole-triazole conjugates for antibiofilm/antibiotic resensitization activity against MRSA and Acinetobacter baumannii. ChemMedChem 6:2243–2251. doi: 10.1002/cmdc.201100316
  98. 98.
    Su ZM, Peng LL, Melander C (2012) A modular approach to the synthesis of 1,4,5-substituted-2-aminoimidazoles. Tetrahedron Lett 53:1204–1206. doi: 10.1016/J.Tetlet.2011.12.090 CrossRefGoogle Scholar
  99. 99.
    Yeagley AA, Su Z, McCullough KD, Worthington RJ, Melander C (2013) N-substituted 2-aminoimidazole inhibitors of MRSA biofilm formation accessed through direct 1,3-bis(tert-butoxycarbonyl)guanidine cyclization. Org Biomol Chem 11:130–137. doi: 10.1039/c2ob26469b PubMedCrossRefGoogle Scholar
  100. 100.
    Harris TL, Worthington RJ, Melander C (2012) Potent small-molecule suppression of oxacillin resistance in methicillin-resistant Staphylococcus aureus. Angew Chem Int Ed 51:11254–11257. doi: 10.1002/anie.201206911 CrossRefGoogle Scholar
  101. 101.
    Klitgaard JK, Skov MN, Kallipolitis BH, Kolmos HJ (2008) Reversal of methicillin resistance in Staphylococcus aureus by thioridazine. J Antimicrob Chemother 62:1215–1221. doi: 10.1093/jac/dkn417 PubMedCrossRefGoogle Scholar
  102. 102.
    Bonde M, Hojland DH, Kolmos HJ, Kallipolitis BH, Klitgaard JK (2011) Thioridazine affects transcription of genes involved in cell wall biosynthesis in methicillin-resistant Staphylococcus aureus. FEMS Microbiol Lett 318:168–176. doi: 10.1111/j.1574-6968.2011.02255.x PubMedCrossRefGoogle Scholar
  103. 103.
    Poulsen MO, Jacobsen K, Thorsing M, Kristensen NR, Clasen J, Lillebaek EM, Skov MN, Kallipolitis BH, Kolmos HJ, Klitgaard JK (2013) Thioridazine potentiates the effect of a β-lactam antibiotic against Staphylococcus aureus independently of mecA expression. Res Microbiol 164:181–188. doi: 10.1016/j.resmic.2012.10.007 PubMedCrossRefGoogle Scholar
  104. 104.
    Harris TL, Worthington RJ, Hittle LE, Zurawski DV, Ernst RK, Melander C (2014) Small molecule downregulation of PmrAB reverses Lipid A modification and breaks colistin resistance. ACS Chem Biol 9:122–127. doi: 10.1021/cb400490k PubMedCrossRefGoogle Scholar
  105. 105.
    Beceiro A, Llobet E, Aranda J, Bengoechea JA, Doumith M, Hornsey M, Dhanji H, Chart H, Bou G, Livermore DM, Woodford N (2011) Phosphoethanolamine modification of lipid A in colistin-resistant variants of Acinetobacter baumannii mediated by the pmrAB two-component regulatory system. Antimicrob Agents Chemother 55:3370–3379. doi: 10.1128/AAC.00079-11 PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Arroyo LA, Herrera CM, Fernandez L, Hankins JV, Trent MS, Hancock RE (2011) The pmrCAB operon mediates polymyxin resistance in Acinetobacter baumannii ATCC 17978 and clinical isolates through phosphoethanolamine modification of lipid A. Antimicrob Agents Chemother 55:3743–3751. doi: 10.1128/AAC.00256-11 PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Brackett CM, Furlani RE, Anderson RG, Krishnamurthy A, Melander RJ, Moskowitz SM, Ernst RK, Melander C (2016) Second generation modifiers of colistin resistance show enhanced activity and lower inherent toxicity. Tetrahedron 72:3549–3553. doi: 10.1016/j.tet.2015.09.019 PubMedCrossRefGoogle Scholar
  108. 108.
    Wilke KE, Francis S, Carlson EE (2015) Inactivation of multiple bacterial histidine kinases by targeting the ATP-binding domain. ACS Chem Biol 10:328–335. doi: 10.1021/cb5008019 PubMedCrossRefGoogle Scholar
  109. 109.
    Boibessot T, Zschiedrich CP, Lebeau A, Benimelis D, Dunyach-Remy C, Lavigne JP, Szurmant H, Benfodda Z, Meffre P (2016) The rational design, synthesis, and antimicrobial properties of thiophene derivatives that inhibit bacterial histidine kinases. J Med Chem 59:8830–8847. doi: 10.1021/acs.jmedchem.6b00580 PubMedCrossRefGoogle Scholar
  110. 110.
    Alam MK, Alhhazmi A, DeCoteau JF, Luo Y, Geyer CR (2016) RecA inhibitors potentiate antibiotic activity and block evolution of antibiotic resistance. Cell Chem Biol 23:381–391. doi: 10.1016/j.chembiol.2016.02.010 PubMedCrossRefGoogle Scholar
  111. 111.
    Reed P, Atilano ML, Alves R, Hoiczyk E, Sher X, Reichmann NT, Pereira PM, Roemer T, Filipe SR, Pereira-Leal JB, Ligoxygakis P, Pinho MG (2015) Staphylococcus aureus survives with a minimal peptidoglycan synthesis machine but sacrifices virulence and antibiotic resistance. PLoS Pathog 11:e1004891. doi: 10.1371/journal.ppat.1004891 PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Campbell J, Singh AK, Santa Maria Jr JP, Kim Y, Brown S, Swoboda JG, Mylonakis E, Wilkinson BJ, Walker S (2011) Synthetic lethal compound combinations reveal a fundamental connection between wall teichoic acid and peptidoglycan biosyntheses in Staphylococcus aureus. ACS Chem Biol 6:106–116. doi: 10.1021/cb100269f PubMedCrossRefGoogle Scholar
  113. 113.
    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.2012.11.013 PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Farha MA, Leung A, Sewell EW, D'Elia MA, Allison SE, Ejim L, Pereira PM, Pinho MG, Wright GD, Brown ED (2013) Inhibition of WTA synthesis blocks the cooperative action of PBPs and sensitizes MRSA to β-lactams. ACS Chem Biol 8(1):226–233. doi: 10.1021/cb300413m PubMedCrossRefGoogle Scholar
  115. 115.
    Labroli MA, Caldwell JP, Yang C, Lee SH, Wang H, Koseoglu S, Mann P, Yang SW, Xiao J, Garlisi CG, Tan C, Roemer T, Su J (2016) Discovery of potent wall teichoic acid early stage inhibitors. Bioorg Med Chem Lett 26:3999–4002. doi: 10.1016/j.bmcl.2016.06.090 PubMedCrossRefGoogle Scholar
  116. 116.
    Mann PA, Muller A, Xiao L, Pereira PM, Yang C, Ho Lee S, 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 Jr 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/cb400487f PubMedCrossRefGoogle Scholar
  117. 117.
    Hurley KA, Santos TM, Nepomuceno GM, Huynh V, Shaw JT, Weibel DB (2016) Targeting the bacterial division protein FtsZ. J Med Chem 59(15):6975–6998. doi: 10.1021/acs.jmedchem.5b01098 PubMedCrossRefGoogle Scholar
  118. 118.
    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 4:126ra135. doi: 10.1126/scitranslmed.3003592 Google Scholar
  119. 119.
    Haydon DJ, Stokes NR, Ure R, Galbraith G, Bennett JM, Brown DR, Baker PJ, Barynin VV, Rice DW, Sedelnikova SE, Heal JR, Sheridan JM, Aiwale ST, Chauhan PK, Srivastava A, Taneja A, Collins I, Errington J, Czaplewski LG (2008) An inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science 321:1673–1675. doi: 10.1126/science.1159961 ADSPubMedCrossRefGoogle Scholar
  120. 120.
    Chan FY, Sun N, Leung YC, Wong KY (2015) Antimicrobial activity of a quinuclidine-based FtsZ inhibitor and its synergistic potential with β-lactam antibiotics. J Antibiot (Tokyo) 68:253–258. doi: 10.1038/ja.2014.140 CrossRefGoogle Scholar
  121. 121.
    Nair DR, Monteiro JM, Memmi G, Thanassi J, Pucci M, Schwartzman J, Pinho MG, Cheung AL (2015) Characterization of a novel small molecule that potentiates β-lactam activity against Gram-positive and Gram-negative pathogens. Antimicrob Agents Chemother 59:1876–1885. doi: 10.1128/AAC.04164-14 PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Lee SH, Jarantow LW, Wang H, Sillaots S, Cheng H, Meredith TC, Thompson J, Roemer T (2011) Antagonism of chemical genetic interaction networks resensitize MRSA to β-lactam antibiotics. Chem Biol 18:1379–1389. doi: 10.1016/j.chembiol.2011.08.015 PubMedCrossRefGoogle Scholar
  123. 123.
    Stapleton PD, Shah S, Anderson JC, Hara Y, Hamilton-Miller JM, Taylor PW (2004) Modulation of β-lactam resistance in Staphylococcus aureus by catechins and gallates. Int J Antimicrob Agents 23:462–467. doi: 10.1016/j.ijantimicag.2003.09.027 PubMedCrossRefGoogle Scholar
  124. 124.
    Bernal P, Lemaire S, Pinho MG, Mobashery S, Hinds J, Taylor PW (2010) Insertion of epicatechin gallate into the cytoplasmic membrane of methicillin-resistant Staphylococcus aureus disrupts penicillin-binding protein (PBP) 2a-mediated β-lactam resistance by delocalizing PBP2. J Biol Chem 285:24055–24065. doi: 10.1074/jbc.M110.114793 PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Rosado H, Turner RD, Foster SJ, Taylor PW (2015) Impact of the β-lactam resistance modifier (–)-epicatechin gallate on the non-random distribution of phospholipids across the cytoplasmic membrane of Staphylococcus aureus. Int J Mol Sci 16:16710–16727. doi: 10.3390/ijms160816710 PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Palacios L, Rosado H, Micol V, Rosato AE, Bernal P, Arroyo R, Grounds H, Anderson JC, Stabler RA, Taylor PW (2014) Staphylococcal phenotypes induced by naturally occurring and synthetic membrane-interactive polyphenolic β-lactam resistance modifiers. PLoS One 9:e93830. doi: 10.1371/journal.pone.0093830 ADSPubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of ChemistryNorth Carolina State UniversityRaleighUSA

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