Overcoming problems of poor drug penetration into bacteria: challenges and strategies for medicinal chemists

Expert Opinion on Drug Discovery

Volumn 13, Issue 6, 2018, Pages 497-507

  Benedetto Tiz, Davide ^a   Kikelj, Danijel ^a   Zidar, Nace ^a  

^a UNIVERSITY OF LJUBLJANA   (Slovenia)

Author keywords

Antibacterial; bacterial cell envelope; bacterial cell wall; drug entry; efflux pump; permeability; physicochemical properties; siderophore

Indexed keywords

ANTIBIOTIC AGENT; LIPOSOME; SIDEROPHORE; ANTIINFECTIVE AGENT;

BACTERIAL CELL WALL; BACTERIAL MEMBRANE; BACTERIUM; CELL MEMBRANE; DRUG DESIGN; DRUG PENETRATION; DRUG UTILIZATION; EUKARYOTIC CELL; HUMAN; PHYSICAL CHEMISTRY; PRACTICE GUIDELINE; PRIORITY JOURNAL; REVIEW; BACTERIAL INFECTION; DRUG EFFECT; METABOLISM; MICROBIOLOGY; PERMEABILITY;

ANTI-BACTERIAL AGENTS; BACTERIA; BACTERIAL INFECTIONS; CELL MEMBRANE; DRUG DESIGN; HUMANS; PERMEABILITY;

EID: 85046891631     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1080/17460441.2018.1455660     Document Type: Review

References (116)

1. Davies J, Davies D., Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev. 2010;74:417–433.
2. Ebejer JP, Charlton MH, Finn PW., Are the physicochemical properties of antibacterial compounds really different from other drugs? J Cheminform. 2016;8:30.
3. Nikaido H. Preventing drug access to targets: cell surface permeability barriers and active efflux in bacteria. Semin Cell Dev Biol. 2001;12:215–223.
4. Davis TD, Gerry CJ, Tan DS. General platform for systematic quantitative evaluation of small-molecule permeability in bacteria. ACS Chem Biol. 2014;9:2535–2544.
5. Silhavy TJ, Kahne D, Walker S. The bacterial cell envelope. Cold Spring Harb Perspect Biol. 2010;2:a000414.
6. Malanovic N, Lohner K. Gram-positive bacterial cell envelopes: the impact on the activity of antimicrobial peptides. Biochim Biophys Acta. 2016;1858:936–946.
7. Jordan S, Hutchings MI, Mascher T. Cell envelope stress response in Gram-positive bacteria. FEMS Microbiol Rev. 2008;32:107–146.
8. Filgueiras MH, Op den Kamp JA. Cardiolipin, a major phospholipid of Gram-positive bacteria that is not readily extractable. Biochim Biophys Acta. 1980;620:332–337.
9. Hayhurst EJ, Kailas L, Hobbs JK, et al. Cell wall peptidoglycan architecture in Bacillus subtilis. Proc Natl Acad Sci USA. 2008;105:14603–14608.
10. Vollmer W, Blanot D, de Pedro MA. Peptidoglycan structure and architecture. FEMS Microbiol Rev. 2008;32:149–167.
11. Neuhaus FC, Baddiley J. A continuum of anionic charge: structures and functions of d-alanyl-teichoic acids in gram-positive bacteria. Microbiol Mol Biol Rev. 2003;67:686–723.
12. D’Elia MA, Millar KE, Beveridge TJ, et al. Wall teichoic acid polymers are dispensable for cell viability in Bacillus subtilis. J Bacteriol. 2006;188:8313–8316.
13. Swoboda JG, Campbell J, Meredith TC, et al. Wall teichoic acid function, biosynthesis, and inhibition. Chembiochem. 2010;11:35–45.
14. Navarre WW, Schneewind O. Surface proteins of gram-positive bacteria and mechanisms of their targeting to the cell wall envelope. Microbiol Mol Biol Rev. 1999;63:174–229.
15. Xia G, Kohler T, Peschel A. The wall teichoic acid and lipoteichoic acid polymers of Staphylococcus aureus. Int J Med Microbiol. 2010;300:148–154.
16. Markham PN, Neyfakh AA. Efflux-mediated drug resistance in Gram-positive bacteria. Curr Opin Microbiol. 2001;4:509–514.
17. Schindler BD, Kaatz GW. Multidrug efflux pumps of Gram-positive bacteria. Drug Resist Updat. 2016;27:1–13.
18. Beveridge TJ. Structures of Gram-negative cell walls and their derived membrane vesicles. J Bacteriol. 1999;181:4725–4733.
19. Delcour AH. Outer membrane permeability and antibiotic resistance. Biochim Biophys Acta. 2009;1794:808–816.
20. Pages JM, James CE, Winterhalter M. The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria. Nat Rev Microbiol. 2008;6:893–903.
21. Narita SI, Tokuda H. Bacterial lipoproteins; biogenesis, sorting and quality control. Biochim Biophys Acta. 2017;1862:1414–1423.
22. Narita S, Matsuyama S, Tokuda H. Lipoprotein trafficking in Escherichia coli. Arch Microbiol. 2004;182:1–6.
23. Wilson MM, Bernstein HD. Surface-exposed lipoproteins: an emerging secretion phenomenon in Gram-negative bacteria. Trends Microbiol. 2016;24:198–208.
24. Amaral L, Martins A, Spengler G, et al. Efflux pumps of Gram-negative bacteria: what they do, how they do it, with what and how to deal with them. Front Pharmacol. 2013;4:168.
25. Li XZ, Nikaido H. Efflux-mediated drug resistance in bacteria: an update. Drugs. 2009;69:1555–1623.
26. Galdiero S, Falanga A, Cantisani M, et al. Microbe-host interactions: structure and role of Gram-negative bacterial porins. Curr Protein Pept Sci. 2012;13:843–854.
27. Fu LM, Fu-Liu CS. Is Mycobacterium tuberculosis a closer relative to Gram-positive or Gram-negative bacterial pathogens? Tuberculosis. 2002;82:85–90.
28. Jackson M. The mycobacterial cell envelope—lipids. Cold Spring Harb Perspect Med. 2014;4:a021105.
29. Daffe M, Draper P. The envelope layers of mycobacteria with reference to their pathogenicity. Adv Microb Physiol. 1998;39:131–203.
30. Jarlier V, Nikaido H. Permeability barrier to hydrophilic solutes in Mycobacterium chelonei. J Bacteriol. 1990;172:1418–1423.
31. Zuber B, Chami M, Houssin C, et al. Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state. J Bacteriol. 2008;190:5672–5680.
32. Bansal-Mutalik R, Nikaido H. Mycobacterial outer membrane is a lipid bilayer and the inner membrane is unusually rich in diacyl phosphatidylinositol dimannosides. Proc Natl Acad Sci USA. 2014;111:4958–4963.
33. Trias J, Jarlier V, Benz R. Porins in the cell wall of mycobacteria. Science. 1992;258:1479–1481.
34. Ojha A, Hatfull GF. The role of iron in Mycobacterium smegmatis biofilm formation: the exochelin siderophore is essential in limiting iron conditions for biofilm formation but not for planktonic growth. Mol Microbiol. 2007;66:468–483.
35. Stahl C, Kubetzko S, Kaps I, et al. MspA provides the main hydrophilic pathway through the cell wall of Mycobacterium smegmatis. Mol Microbiol. 2001;40:451–464.
36. Wolschendorf F, Mahfoud M, Niederweis M. Porins are required for uptake of phosphates by Mycobacterium smegmatis. J Bacteriol. 2007;189:2435–2442.
37. Stephan J, Bender J, Wolschendorf F, et al. The growth rate of Mycobacterium smegmatis depends on sufficient porin-mediated influx of nutrients. Mol Microbiol. 2005;58:714–730.
38. Chiaradia L, Lefebvre C, Parra J, et al. Dissecting the mycobacterial cell envelope and defining the composition of the native mycomembrane. Sci Rep. 2017;7:12807.
39. Ramon-Garcia S, Martín C, Thompson CJ, et al. Role of the Mycobacterium tuberculosis P55 efflux pump in intrinsic drug resistance, oxidative stress responses, and growth. Antimicrob Agents Chemother. 2009;53:3675–3682.
40. Viveiros M, Martins M, Rodrigues L, et al. Inhibitors of mycobacterial efflux pumps as potential boosters for anti-tubercular drugs. Expert Rev Anti-Infect Ther. 2012;10:983–998.
41. Liu J, Takiff HE, Nikaido H. Active efflux of fluoroquinolones in Mycobacterium smegmatis mediated by LfrA, a multidrug efflux pump. J Bacteriol. 1996;178:3791–3795.
42. McMurry L, Petrucci RE, Levy SB. Active efflux of tetracycline encoded by four genetically different tetracycline resistance determinants in Escherichia coli. PNAS. 1980;77:3974–3977.
43. Hernando-Amado S, Blanco P, Alcalde-Rico M, et al. Multidrug efflux pumps as main players in intrinsic and acquired resistance to antimicrobials. Drug Resist Updat. 2016;28:13–27.
44. Paulsen IT, Sliwinski MK, Saier MH, Jr. Microbial genome analyses: global comparisons of transport capabilities based on phylogenies, bioenergetics and substrate specificities. J Mol Biol. 1998;277:573–592.
45. Kumar A, Schweizer HP. Bacterial resistance to antibiotics: active efflux and reduced uptake. Adv Drug Deliv Rev. 2005;57:1486–1513.
46. Sun J, Deng Z, Yan A. Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations. Biochem Biophys Res Commun. 2014;453:254–267.
47. Marquez B. Bacterial efflux systems and efflux pumps inhibitors. Biochimie. 2005;87:1137–1147.
48. Moreira MAS, de Souza EC, de Moraes CA. Multidrug efflux systems in Gram-negative bacteria. Braz J Microbiol. 2004;35:19–28.
49. Blanco P, Hernando-Amado S, Reales-Calderon JA, et al. Bacterial multidrug efflux pumps: much more than antibiotic resistance determinants. Microorg. 2016;4:1–19.
50. Krishnamoorthy G, Leus IV, Weeks JW, et al. Synergy between active efflux and outer membrane diffusion defines rules of antibiotic permeation into Gram-negative bacteria. Mbio. 2017;8:1–16.
51. Fralick JA. Evidence that TolC is required for functioning of the Mar/AcrAB efflux pump of Escherichia coli. J Bacteriol. 1996;178:5803–5805.
52. Piddock LJ. Multidrug-resistance efflux pumps - not just for resistance. Nat Rev Microbiol. 2006;4:629–636.
53. Du D, Wang Z, James NR, et al. Structure of the AcrAB-TolC multidrug efflux pump. Nature. 2014;509:512–515.
54. Silver LL. Challenges of antibacterial discovery. Clin Microbiol Rev. 2011;24:71–109.
55. Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 1997;23:3–25.
56. O’Shea R, Moser HE. Physicochemical properties of antibacterial compounds: implications for drug discovery. J Med Chem. 2008;51:2871–2878.
57. Leeson PD, Davis AM. Time-related differences in the physical property profiles of oral drugs. J Med Chem. 2004;47:6338–6348.
58. Silver LL. A gestalt approach to Gram-negative entry. Bioorg Med Chem. 2016;24:6379–6389.
59. Vaara M. Agents that increase the permeability of the outer membrane. Microbiol Rev. 1992;56:395–411.
60. Van Bambeke F, Pages JM, Lee VJ. Inhibitors of bacterial efflux pumps as adjuvants in antibiotic treatments and diagnostic tools for detection of resistance by efflux. Recent Pat Antiinfect Drug Discov. 2006;1:157–175.
61. Lamers RP, Cavallari JF, Burrows LL. The efflux inhibitor phenylalanine-arginine beta-naphthylamide (PAβN) permeabilizes the outer membrane of Gram-negative bacteria. PLoS One. 2013;8:e60666.
62. Okandeji BO, Greenwald DM, Wroten J, et al. Synthesis and evaluation of inhibitors of bacterial drug efflux pumps of the major facilitator superfamily. Bioorg Med Chem. 2011;19:7679–7689.
63. Lomovskaya O, Warren MS, Lee A, et al. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrob Agents Ch. 2001;45:105–116.
64. Renau TE, Leger R, Flamme EM, et al. Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of the fluoroquinolone antibacterial levofloxacin. J Med Chem. 1999;42:4928–4931.
65. Lambert PA. Cellular impermeability and uptake of biocides and antibiotics in Gram-positive bacteria and mycobacteria. J Appl Microbiol. 2002;92:46–54.
66. Manchester JI, Buurman ET, Bisacchi GS, et al. Molecular determinants of AcrB-mediated bacterial efflux implications for drug discovery. J Med Chem. 2012;55:2532–2537.
67. Bisacchi GS, Manchester JI. A new-class antibacterial-almost. Lessons in drug discovery and development: a critical analysis of more than 50 years of effort toward ATPase inhibitors of DNA gyrase and topoisomerase IV. ACS Infect Dis. 2015;1:4–41.
68. Manchester JI, Dussault DD, Rose JA, et al. Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and topoisomerase IV. Bioorg Med Chem Lett. 2012;22:5150–5156.
69. Richter MF, Drown BS, Riley AP, et al. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature. 2017;545:299–304.
70. Kuenemann MA, Bourbon LM, Labbe CM, et al. Which three-dimensional characteristics make efficient inhibitors of protein-protein interactions? J Chem Inf Model. 2014;54:3067–3079.
71. Delcour AH. Outer membrane permeability and antibiotic resistance. Biochim Biophys Acta-Proteins Proteomics. 2009;1794:808–816.
72. Hancock RE. Alterations in outer membrane permeability. Annu Rev Microbiol. 1984;38:237–264.
73. Daugelavičius R, Bakienė E, Bamford DH. Stages of polymyxin B interaction with the Escherichia coli cell envelope. Antimicrob Agents Chemother. 2000;44:2969–2978.
74. Nikaido H, Thanassi DG. Penetration of lipophilic agents with multiple protonation sites into bacterial cells: tetracyclines and fluoroquinolones as examples. Antimicrob Agents Chemother. 1993;37:1393–1399.
75. Nikaido H, Vaara M. Molecular basis of bacterial outer membrane permeability. Microbiol Rev. 1985;49:1–32.
76. Leive L, Telesetsky S, Coleman WG, et al. Tetracyclines of various hydrophobicities as a probe for permeability of Escherichia coli outer membranes. Antimicrob Agents Chemother. 1984;25:539–544.
77. Denis O, Rodriguez-Villalobos H, Struelens MJ. Chapter 3 - the problem of resistance A2. In: Finch RG, Greenwood D, Norrby SR, et al., editors. Antibiotic and chemotherapy. 9th ed. London: Elsevier Saunders; 2010.:24–48.
78. Kaufman MB. Pharmaceutical Approval Update. P T. 2017;42:673–683.
79. Markham A. Delafloxacin: first global approval. Drugs. 2017;77:1481–1486.
80. Candel FJ, Penuelas M. Delafloxacin: design, development and potential place in therapy. Drug Des Devel Ther. 2017;11:881–891.
81. Zgurskaya HI, Löpez CA, Gnanakaran S. Permeability barrier of Gram-negative cell envelopes and approaches to bypass it. ACS Infect Dis. 2015;1:512–522.
82. Chu BC, Garcia-Herrero A, Johanson TH, et al. Siderophore uptake in bacteria and the battle for iron with the host; a bird’s eye view. Biometals. 2010;23:601–611.
83. Page MGP. Siderophore conjugates. Annals NY Acad Sci. 2013;1277:115–126.
84. Saha R, Saha N, Donofrio RS, et al. Microbial siderophores: a mini review. J Basic Microbiol. 2013;53:303–317.
85. Ferreira D, Seca AM, Gad C, et al. Targeting human pathogenic bacteria by siderophores: a proteomics review. J Proteomics. 2016;145:153–166.
86. De Carvalho CCCR, Fernandes P. Siderophores as “Trojan Horses”: tackling multidrug resistance? Front Microbiol. 2014;5:290.
87. Ghosh M, Miller MJ. Design, synthesis, and biological evaluation of isocyanurate-based antifungal and macrolide antibiotic conjugates: iron transport-mediated drug delivery. Bioorg Med Chem. 1995;3:1519–1525.
88. Md-Saleh SR, Chilvers EC, Kerr KG, et al. Synthesis of citrate-ciprofloxacin conjugates. Bioorg Med Chem Lett. 2009;19:1496–1498.
89. Ji C, Miller MJ. Chemical syntheses and in vitro antibacterial activity of two desferrioxamine B-ciprofloxacin conjugates with potential esterase and phosphatase triggered drug release linkers. Bioorg Med Chem. 2012;20:3828–3836.
90. Page MGP, Dantier C, Desarbre E. In vitro properties of BAL30072, a novel siderophore sulfactam with activity against multiresistant Gram-negative bacilli. Antimicrob Agents Chemother. 2010;54:2291–2302.
91. Monogue ML, Tsuji M, Yamano Y, et al. Efficacy of humanized exposures of cefiderocol (S-649266) against a diverse population of Gram-negative bacteria in a murine thigh infection model. Antimicrob Agents Chemother. 2017;61:1–10.
92. Pages JM, Masi M, Barbe J. Inhibitors of efflux pumps in Gram-negative bacteria. Trends Mol Med. 2005;11:382–389.
93. Zhang Z, Liu Z-Q, Zheng P-Y, et al. Influence of efflux pump inhibitors on the multidrug resistance of Helicobacter pylori. World J Gastroenterol. 2010;16:1279–1284.
94. Olivares J, Bernardini A, Garcia-Leon G, et al. The intrinsic resistome of bacterial pathogens. Front Microbiol. 2013;4:103.
95. Masi M, Refregiers M, Pos KM, et al. Mechanisms of envelope permeability and antibiotic influx and efflux in Gram-negative bacteria. Nat Microbiol. 2017;2:17001.
96. Lomovskaya O, Warren MS, Lee A, et al. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrob Agents Chemother. 2001;45:105–116.
97. Sanchez P, Le U, Martinez JL. The efflux pump inhibitor Phe-Arg-beta-naphthylamide does not abolish the activity of the Stenotrophomonas maltophilia SmeDEF multidrug efflux pump. J Antimicrob Chemother. 2003;51:1042–1045.
98. Lomovskaya O, Bostian KA. Practical applications and feasibility of efflux pump inhibitors in the clinic–a vision for applied use. Biochem Pharmacol. 2006;71:910–918.
99. Nakayama K, Ishida Y, Ohtsuka M, et al. MexAB-OprM-specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: discovery and early strategies for lead optimization. Bioorg Med Chem Lett. 2003;13:4201–4204.
100. Yoshida K, Nakayama K, Ohtsuka M, et al. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 7: highly soluble and in vivo active quaternary ammonium analogue D13-9001, a potential preclinical candidate. Bioorg Med Chem. 2007;15:7087–7097.
101. Bohnert JA, Kern WV. Selected arylpiperazines are capable of reversing multidrug resistance in Escherichia coli overexpressing RND efflux pumps. Antimicrob Agents Chemother. 2005;49:849–852.
102. Sabatini S, Gosetto F, Manfroni G, et al. Evolution from a natural flavones nucleus to obtain 2-(4-propoxyphenyl)quinoline derivatives as potent inhibitors of the S. aureus NorA efflux pump. J Med Chem. 2011;54:5722–5736.
103. Poisson J, Le Hir A, Goutarel R, et al. Isolation of reserpine from roots of Rauwolfia vomitoria Afz. C R Hebd Seances Acad Sci. 1954;238:1607–1609.
104. Neyfakh AA, Bidnenko VE, Chen LB. Efflux-mediated multidrug resistance in Bacillus subtilis: similarities and dissimilarities with the mammalian system. PNAS. 1991;88:4781–4785.
105. Kumar S, Mukherjee MM, Varela MF. Modulation of bacterial multidrug resistance efflux pumps of the major facilitator superfamily. Int J Bacteriol. 2013;pii:2041412013.
106. Mullin S, Mani N, Grossman TH. Inhibition of antibiotic efflux in bacteria by the novel multidrug resistance inhibitors biricodar (VX-710) and timcodar (VX-853). Antimicrob Agents Chemother. 2004;48:4171–4176.
107. Handzlik J, Matys A, Kieć-Kononowicz K. Recent advances in multi-drug resistance (MDR) efflux pump inhibitors of Gram-positive bacteria S. aureus. Antibiotics. 2013;2:28–45.
108. Pinto-Alphandary H, Andremont A, Couvreur P. Targeted delivery of antibiotics using liposomes and nanoparticles: research and applications. Int J Antimicrob Agents. 2000;13:155–168.
109. Abed N, Couvreur P. Nanocarriers for antibiotics: a promising solution to treat intracellular bacterial infections. Int J Antimicrob Agents. 2014;43:485–496.
110. Drulis-Kawa Z, Dorotkiewicz-Jach A. Liposomes as delivery systems for antibiotics. Int J Pharm. 2010;387:187–198.
111. Nicolosi D, Cupri S, Genovese C, et al. Nanotechnology approaches for antibacterial drug delivery: preparation and microbiological evaluation of fusogenic liposomes carrying fusidic acid. Int J Antimicrob Agents. 2015;45:622–626.
112. Elhissi A. Liposomes for pulmonary drug delivery: the role of formulation and inhalation device design. Curr Pharm Des. 2017;23:362–372.
113. Sharma A, Sharma US. Liposomes in drug delivery: progress and limitations. Int J Pharm. 1997;154:123–140.
114. Parkin J, Chavent M, Khalid S. Molecular simulations of Gram-negative bacterial membranes: a vignette of some recent successes. Biophys J. 2015;109:461–468.
115. Iyer R, Sylvester MA, Velez-Vega C, et al. Whole-cell-based assay to evaluate structure permeation relationships for carbapenem passage through the Pseudomonas aeruginosa Porin OprD. ACS Infect Dis. 2017;3:310–319.
116. Stokes JM, MacNair CR, Ilyas B, et al. Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance. Nature Microbiol. 2017;2:1–21.