Synergy between active efflux and outer membrane diffusion defines rules of antibiotic permeation into gram-negative bacteria

mBio

Volumn 8, Issue 5, 2017, Pages

  Krishnamoorthy, Ganesh ^a   Leus, Inga V ^a   Weeks, Jon W ^a   Wolloscheck, David ^a   Rybenkov, Valentin V ^a   Zgurskaya, Helen I ^a  

^a UNIVERSITY OF OKLAHOMA   (United States)

Author keywords

Acinetobacter; Antibiotic resistance; Burkholderia; Multidrug efflux; Outer membrane; Permeability barrier; Pseudomonas aeruginosa

Indexed keywords

AMIKACIN; AMPICILLIN; ANTIBIOTIC AGENT; AZITHROMYCIN; BACITRACIN; BACTERIAL PROTEIN; BTPORE PROTEIN; CARBENICILLIN; CHLORAMPHENICOL; CIPROFLOXACIN; CLOXACILLIN; ECPORE PROTEIN; ERYTHROMYCIN; HOE 33342; LEVOFLOXACIN; MAGNESIUM ION; MEROPENEM; NALIDIXIC ACID; NOVOBIOCIN; PHLEOMYCIN; POLYMYXIN B; PORIN; RIFAMPICIN; TETRACYCLINE; TOBRAMYCIN; TRICLOSAN; UNCLASSIFIED DRUG; VANCOMYCIN; ANTIINFECTIVE AGENT; OUTER MEMBRANE PROTEIN;

ACINETOBACTER BAUMANNII; ANTIBACTERIAL ACTIVITY; ANTIBIOTIC RESISTANCE; ANTIBIOTIC SENSITIVITY; ARTICLE; BACTERIAL OUTER MEMBRANE; BURKHOLDERIA CEPACIA; BURKHOLDERIA THAILANDENSIS; CELL KILLING; CELL MEMBRANE PERMEABILITY; CONTROLLED STUDY; DIFFUSION; DRUG PENETRATION; EFFUSION; GRAM NEGATIVE BACTERIUM; HYPERPORINATION; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; PERMEABILITY BARRIER; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN MODIFICATION; PSEUDOMONAS AERUGINOSA; CHEMISTRY; DRUG EFFECT; HUMAN; METABOLISM; MULTIDRUG RESISTANCE; PATHOGENICITY; PERMEABILITY; TRANSPORT AT THE CELLULAR LEVEL;

ACINETOBACTER BAUMANNII; ANTI-BACTERIAL AGENTS; BACTERIAL OUTER MEMBRANE PROTEINS; BIOLOGICAL TRANSPORT; BURKHOLDERIA CEPACIA; DIFFUSION; DRUG RESISTANCE, MULTIPLE, BACTERIAL; GRAM-NEGATIVE BACTERIA; HUMANS; PERMEABILITY; PORINS; PSEUDOMONAS AERUGINOSA;

EID: 85033713759     PISSN: 21612129     EISSN: 21507511     Source Type: Journal    
DOI: 10.1128/mBio.01172-17     Document Type: Article

References (67)

1. Innovative Medicines Initiative. 2013. Innovative Medicines Initiative: translocation. http://www.imi.europa.eu/projects-results/project-factsheets/translocation.
2. Sánchez S, Demain AL (ed). 2015. Antibiotics: current innovations and future trends. Caister Academic Press, Norfolk, United Kingdom.
3. Nikaido H. 2003. Molecular basis of bacterial outer membrane permeability revisited. Microbiol Mol Biol Rev 67:593–656. https://doi.org/10.1128/MMBR.67.4.593-656.2003.
4. Henderson JC, Zimmerman SM, Crofts AA, Boll JM, Kuhns LG, Herrera CM, Trent MS. 2016. The power of asymmetry: architecture and assembly of the Gram-negative outer membrane lipid bilayer. Annu Rev Microbiol 70:255–278. https://doi.org/10.1146/annurev-micro-102215-095308.
5. Nascimento A, Pontes FJS, Lins RD, Soares TA. 2014. Hydration, ionic valence and cross-linking propensities of cations determine the stability of lipopolysaccharide (LPS) membranes. Chem Commun 50:231–233. https://doi.org/10.1039/c3cc46918b.
6. Dias RP, da Hora GC, Ramstedt M, Soares TA. 2014. Outer membrane remodeling: the structural dynamics and electrostatics of rough lipopolysaccharide chemotypes. J Chem Theory Comput 10:2488–2497. https://doi.org/10.1021/ct500075h.
7. Faunce CA, Reichelt H, Paradies HH, Quitschau P, Zimmermann K. 2005. The liquidlike ordering of lipid A-diphosphate colloidal crystals: the influence of Ca2+, Mg2+, Na+, and K+ on the ordering of colloidal suspensions of lipid A-diphosphate in aqueous solutions. J Chem Phys 122:214727. https://doi.org/10.1063/1.1913477.
8. O’Shea R, Moser HE. 2008. Physicochemical properties of antibacterial compounds: implications for drug discovery. J Med Chem 51:2871–2878. https://doi.org/10.1021/jm700967e.
9. Nikaido H. 2001. Preventing drug access to targets: cell surface permeability barriers and active efflux in bacteria. Semin Cell Dev Biol 12: 215–223. https://doi.org/10.1006/scdb.2000.0247.
10. Lakaye B, Dubus A, Joris B, Frère JM. 2002. Method for estimation of low outer membrane permeability to β-lactam antibiotics. Antimicrob Agents Chemother 46:2901–2907. https://doi.org/10.1128/AAC.46.9.2901 -2907.2002.
11. Lomovskaya O, Zgurskaya HI, Bostian KA. 2008. Bacterial multidrug transporters: molecular and clinical aspects, p 121–158, in press. In Ecker GF, Chiba P (ed), Transporters as drug carriers, vol. 33. Wiley & Sons, Hoboken, NJ.
12. Nikaido H, Zgurskaya HI. 1999. Antibiotic efflux mechanisms. Curr Opin Infect Dis 12:529–536. https://doi.org/10.1097/00001432-199912000-00001.
13. Zgurskaya HI, Löpez CA, Gnanakaran S. 2015. Permeability barrier of Gram-negative cell envelopes and approaches to bypass it. ACS Infect Dis 1:512–522. https://doi.org/10.1021/acsinfecdis.5b00097.
14. Lee A, Mao W, Warren MS, Mistry A, Hoshino K, Okumura R, Ishida H, Lomovskaya O. 2000. Interplay between efflux pumps may provide either additive or multiplicative effects on drug resistance. J Bacteriol 182:3142–3150. https://doi.org/10.1128/JB.182.11.3142-3150.2000.
15. Shuster Y, Steiner-Mordoch S, Alon Cudkowicz N, Schuldiner S. 2016. A transporter interactome is essential for the acquisition of antimicrobial resistance to antibiotics. PLoS One 11:e0152917. https://doi.org/10.1371/journal.pone.0152917.
16. Fluman N, Ryan CM, Whitelegge JP, Bibi E. 2012. Dissection of mechanistic principles of a secondary multidrug efflux protein. Mol Cell 47: 777–787. https://doi.org/10.1016/j.molcel.2012.06.018.
17. Zgurskaya HI, Weeks JW, Ntreh AT, Nickels LM, Wolloscheck D. 2015. Mechanism of coupling drug transport reactions located in two different membranes. Front Microbiol 6:100. https://doi.org/10.3389/fmicb.2015.00100.
18. Beinlich KL, Chuanchuen R, Schweizer HP. 2001. Contribution of multidrug efflux pumps to multiple antibiotic resistance in veterinary clinical isolates of Pseudomonas aeruginosa. FEMS Microbiol Lett 198:129–134. https://doi.org/10.1111/j.1574-6968.2001.tb10631.x.
19. Mazzariol A, Tokue Y, Kanegawa TM, Cornaglia G, Nikaido H. 2000. High-level fluoroquinolone-resistant clinical isolates of Escherichia coli overproduce multidrug efflux protein AcrA. Antimicrob Agents Chemother 44:3441–3443. https://doi.org/10.1128/AAC.44.12.3441-3443.2000.
20. Pagdepanichkit S, Tribuddharat C, Chuanchuen R. 2016. Distribution and expression of the Ade multidrug efflux systems in Acinetobacter bau- mannii clinical isolates. Can J Microbiol 62:794–801. https://doi.org/10.1139/cjm-2015-0730.
21. Brown DG, May-Dracka TL, Gagnon MM, Tommasi R. 2014. Trends and exceptions of physical properties on antibacterial activity for Gram-positive and Gram-negative pathogens. J Med Chem 57:10144–10161. https://doi.org/10.1021/jm501552x.
22. Manchester JI, Buurman ET, Bisacchi GS, McLaughlin RE. 2012. Molecular determinants of AcrB-mediated bacterial efflux implications for drug discovery. J Med Chem 55:2532–2537. https://doi.org/10.1021/jm201275d.
23. Nikaido H, Basina M, Nguyen V, Rosenberg EY. 1998. Multidrug efflux pump AcrAB of Salmonella typhimurium excretes only those beta-lactam antibiotics containing lipophilic side chains. J Bacteriol 180: 4686–4692.
24. Westfall DA, Krishnamoorthy G, Wolloscheck D, Sarkar R, Zgurskaya HI, Rybenkov VV. 2017. Bifurcation kinetics of drug uptake by Gram-negative bacteria. PLoS One 12:e0184671. https://doi.org/10.1371/journal.pone.0184671.
25. Krishnamoorthy G, Wolloscheck D, Weeks JW, Croft C, Rybenkov VV, Zgurskaya HI. 2016. Breaking the permeability barrier of Escherichia coli by controlled hyperporination of the outer membrane. Antimicrob Agents Chemother 60:7372–7381. https://doi.org/10.1128/AAC.01882-16.
26. Nichols WW. 2017. Modeling the kinetics of the permeation of antibacterial agents into growing bacteria and its interplay with efflux. Antimicrob Agents Chemother 61 https://doi.org/10.1128/AAC.02576-16.
27. Silver LL. 2011. Challenges of antibacterial discovery. Clin Microbiol Rev 24:71–109. https://doi.org/10.1128/CMR.00030-10.
28. Lewis K. 2012. Antibiotics: recover the lost art of drug discovery. Nature 485:439–440. https://doi.org/10.1038/485439a.
29. The Pew Charitable Trusts. 2016. A scientific roadmap for antibiotic discovery: a sustainable and robust pipeline of new antibacterial drugs and therapies is critical to preserve public health. Antibiotic Resistance Project. http://www.pewtrusts.org/en/research-and-analysis/reports/2016/05/a-scientific-roadmap-for-antibiotic-discovery.
30. Richter MF, Drown BS, Riley AP, Garcia A, Shirai T, Svec RL, Hergenrother PJ. 2017. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 545:299–304. https://doi.org/10.1038/nature22308.
31. Davis TD, Gerry CJ, Tan DS. 2014. General platform for systematic quantitative evaluation of small-molecule permeability in bacteria. ACS Chem Biol 9:2535–2544. https://doi.org/10.1021/cb5003015.
32. Mohammad MM, Howard KR, Movileanu L. 2011. Redesign of a plugged beta-barrel membrane protein. J Biol Chem 286:8000–8013. https://doi.org/10.1074/jbc.M110.197723.
33. Sokol PA, Darling P, Lewenza S, Corbett CR, Kooi CD. 2000. Identification of a siderophore receptor required for ferric ornibactin uptake in Burkholderia cepacia. Infect Immun 68:6554–6560. https://doi.org/10.1128/IAI.68.12.6554-6560.2000.
34. Lomovskaya O, Lee A, Hoshino K, Ishida H, Mistry A, Warren MS, Boyer E, Chamberland S, Lee VJ. 1999. Use of a genetic approach to evaluate the consequences of inhibition of efflux pumps in Pseudomonas aeruginosa. Antimicrob Agents Chemother 43:1340–1346.
35. Biot FV, Lopez MM, Poyot T, Neulat-Ripoll F, Lignon S, Caclard A, Thibault FM, Peinnequin A, Pagès JM, Valade E. 2013. Interplay between three RND efflux pumps in doxycycline-selected strains of Burkholderia thailandensis. PLoS One 8:e84068. https://doi.org/10.1371/journal.pone.0084068.
36. Shapiro AB, Ling V. 1997. Extraction of Hoechst 33342 from the cytoplasmic leaflet of the plasma membrane by P-glycoprotein. Eur J Biochem 250: 122–129. https://doi.org/10.1111/j.1432-1033.1997.00122.x.
37. Coldham NG, Webber M, Woodward MJ, Piddock LJV. 2010. A 96-well plate fluorescence assay for assessment of cellular permeability and active efflux in Salmonella enterica serovar Typhimurium and Escherichia coli. J Antimicrob Chemother 65:1655–1663. https://doi.org/10.1093/jac/dkq169.
38. Richmond GE, Chua KL, Piddock LJV. 2013. Efflux in Acinetobacter baumannii can be determined by measuring accumulation of H33342 (bis-benzamide). J Antimicrob Chemother 68:1594–1600. https://doi.org/10.1093/jac/dkt052.
39. Loh B, Grant C, Hancock RE. 1984. Use of the fluorescent probe 1-N-phenylnaphthylamine to study the interactions of aminoglycoside antibiotics with the outer membrane of Pseudomonas aeruginosa. Antimi- crob Agents Chemother 26:546–551. https://doi.org/10.1128/AAC.26.4.546.
40. Chen AY, Yu C, Bodley A, Peng LF, Liu LF. 1993. A new mammalian DNA topoisomerase I poison Hoechst 33342: cytotoxicity and drug resistance in human cell cultures. Cancer Res 53:1332–1337.
41. Müller H, Klinkhammer W, Globisch C, Kassack MU, Pajeva IK, Wiese M. 2007. New functional assay of P-glycoprotein activity using Hoechst 33342. Bioorg Med Chem 15:7470–7479. https://doi.org/10.1016/j.bmc.2007.07.024.
42. Iyer R, Sylvester MA, Velez-Vega C, Tommasi R, Durand-Reville TF, Miller AA. 2017. Whole-cell-based assay to evaluate structure permeation relationships for carbapenem passage through the Pseudomonas aeruginosa porin OprD. ACS Infect Dis 3:310–319. https://doi.org/10.1021/acsinfecdis.6b00197.
43. Zahn M, D’Agostino T, Eren E, Baslé A, Ceccarelli M, van den Berg B. 2015. Small-molecule transport by CarO, an abundant eight-stranded β-barrel outer membrane protein from Acinetobacter baumannii. J Mol Biol 427:2329–2339. https://doi.org/10.1016/j.jmb.2015.03.016.
44. Hancock RE. 1981. Aminoglycoside uptake and mode of action-with special reference to streptomycin and gentamicin. II. Effects of aminoglycosides on cells. J Antimicrob Chemother 8:429–445. https://doi.org/10.1093/jac/8.6.429.
45. Jo JT, Brinkman FS, Hancock RE. 2003. Aminoglycoside efflux in Pseudomonas aeruginosa: involvement of novel outer membrane proteins. Antimicrob Agents Chemother 47:1101–1111. https://doi.org/10.1128/AAC.47.3.1101-1111.2003.
46. Schurek KN, Marr AK, Taylor PK, Wiegand I, Semenec L, Khaira BK, Hancock RE. 2008. Novel genetic determinants of low-level aminoglycoside resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 52:4213–4219. https://doi.org/10.1128/AAC.00507-08.
47. Tamber S, Hancock RE. 2004. The outer membranes of pseudomonads, p 575–601. In Ramos J-L (ed), Pseudomonas, vol. 1. Kluwer Academic/ Plenum Publishers, New York, NY.
48. Sugawara E, Nestorovich EM, Bezrukov SM, Nikaido H. 2006. Pseudomonas aeruginosa porin OprF exists in two different conformations. J Biol Chem 281:16220–16229. https://doi.org/10.1074/jbc.M600680200.
49. Hancock REW, Siehnel R, Martin N. 1990. Outer membrane proteins of Pseudomonas. Mol Microbiol 4:1069–1075. https://doi.org/10.1111/j.1365-2958.1990.tb00680.x.
50. Borneleit P, Kleber H-P. 1991. The outer membrane of Acinetobacter: structure-function relationships, p 259–272. In Towner KJ, Bergogne-Berezin E, Fewson CA (ed), The biology of Acinetobacter. Plenum Press, New York, NY.
51. Pelletier MR, Casella LG, Jones JW, Adams MD, Zurawski DV, Hazlett KRO, 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:.
52. Novem V, Shui G, Wang D, Bendt AK, Sim SH, Liu Y, Thong TW, Sival-ingam SP, Ooi EE, Wenk MR, Tan G. 2009. Structural and biological diversity of lipopolysaccharides from Burkholderia pseudomallei and Burkholderia thailandensis. Clin Vaccine Immunol 16:1420–1428. https://doi.org/10.1128/CVI.00472-08.
53. Vinion-Dubiel AD, Goldberg JB. 2003. Review: lipopolysaccharide of Burkholderia cepacia complex. J Endotoxin Res 9:201–213.
54. 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 phosphoe- thanolamine modification of lipid A. Antimicrob Agents Chemother 55:3743–3751. https://doi.org/10.1128/AAC.00256-11.
55. Moore RA, Hancock RE. 1986. Involvement of outer membrane of Pseudomonas cepacia in aminoglycoside and polymyxin resistance. Antimicrob Agents Chemother 30:923–926. https://doi.org/10.1128/AAC.30.6.923.
56. Moskowitz SM, Brannon MK, Dasgupta N, Pier M, Sgambati N, Miller AK, Selgrade SE, Miller SI, Denton M, Conway SP, Johansen HK, Høiby N. 2012. PmrB mutations promote polymyxin resistance of Pseudomonas aeruginosa isolated from colistin-treated cystic fibrosis patients. Antimicrob Agents Chemother 56:1019–1030. https://doi.org/10.1128/AAC.05829-11.
57. Olaitan AO, Morand S, Rolain JM. 2014. Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria. Front Microbiol 5:643. https://doi.org/10.3389/fmicb.2014.00643.
58. Tommasi R, Brown DG, Walkup GK, Manchester JI, Miller AA. 2015. ESKAPEing the labyrinth of antibacterial discovery. Nat Rev Drug Discov 14:529–542. https://doi.org/10.1038/nrd4572.
59. Eicher T, Cha HJ, Seeger MA, Brandstätter L, El-Delik J, Bohnert JA, Kern WV, Verrey F, Grütter MG, Diederichs K, Pos KM. 2012. Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop. Proc Natl Acad Sci U S A 109:5687–5692. https://doi.org/10.1073/pnas.1114944109.
60. Eicher T, Seeger MA, Anselmi C, Zhou W, Brandstätter L, Verrey F, Diederichs K, Faraldo-Gómez JD, Pos KM. 2014. Coupling of remote alternating-access transport mechanisms for protons and substrates in the multidrug efflux pump AcrB. Elife 3:e03145. https://doi.org/10.7554/eLife.03145.
61. Yoon EJ, Chabane YN, Goussard S, Snesrud E, Courvalin P, Dé E, Grillot-Courvalin C. 2015. Contribution of resistance-nodulation-cell division efflux systems to antibiotic resistance and biofilm formation in Acinetobacter baumannii. mBio 6:e00309-15. https://doi.org/10.1128/mBio.00309-15.
62. Sobel ML, Hocquet D, Cao L, Plesiat P, Poole K. 2005. Mutations in PA3574 (nalD) lead to increased MexAB-OprM expression and multidrug resistance in laboratory and clinical isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother 49:1782–1786. https://doi.org/10.1128/AAC.49.5.1782-1786.2005.
63. Guglierame P, Pasca MR, De Rossi E, Buroni S, Arrigo P, Manina G, Riccardi G. 2006. Efflux pump genes of the resistance-nodulation-division family in Burkholderia cenocepacia genome. BMC Microbiol 6:66. https://doi.org/10.1186/1471-2180-6-66.
64. Podnecky N, Rhodes K, Schweizer H. 2015. Efflux pump-mediated drug resistance in Burkholderia. Front Microbiol 6. https://doi.org/10.3389/fmicb.2015.00305.
65. Buroni S, Matthijs N, Spadaro F, Van Acker H, Scoffone VC, Pasca MR, Riccardi G, Coenye T. 2014. Differential roles of RND efflux pumps in antimicrobial drug resistance of sessile and planktonic Burkholderia cenocepacia cells. Antimicrob Agents Chemother 58:7424–7429. https://doi.org/10.1128/AAC.03800-14.
66. Chan YY, Chua KL. 2005. The Burkholderia pseudomallei BpeAB-OprB efflux pump: expression and impact on quorum sensing and virulence. J Bacteriol 187:4707–4719. https://doi.org/10.1128/JB.187.14.4707-4719.2005.
67. Halkidi M, Batistakis Y, Vazirgiannis M. 2001. On clustering validation techniques. J Intell Inform Syst 17:107–145. https://doi.org/10.1023/A:1012801612483.