Bacterial efflux pump inhibition

Current Opinion in Investigational Drugs

Volumn 6, Issue 2, 2005, Pages 191-198

  Kaatz, Glenn W ^a  

^a WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Drug efflux; Efflux pump inhibitor; Multidrug resistance

Indexed keywords

1,1 DIMETHYL 5 (1 HYDROXYPROPYL) 4,6,7 TRIMETHYLINDAN; 13 CYCLOPENTYLTHIO 5 HYDROXYTETRACYCLINE; ABC TRANSPORTER; ANTIBIOTIC AGENT; BACTERIAL PROTEIN; BENZIMIDAZOLE DERIVATIVE; CARRIER PROTEIN; INDAN DERIVATIVE; LEVOFLOXACIN; MC 002434; MC 02595; MC 04112; MC 04124; MC 510051; MEMBRANE PROTEIN; NALIDIXIC ACID; NICORDAMINE; PHENYLALANYLARGININE 2 NAPHTHYLAMIDE; POLYPEPTIDE ANTIBIOTIC AGENT; PROTEIN DRUG METABOLITE TRANSPORTER; PROTEIN MAJOR FACILITATOR SUPERFAMILY; PROTEIN MULTIPLE ANTIBIOTIC AND TOXIN EXTRUSION; PROTEIN RESISTANCE NODULATION DIVISION; RESERPINE; RO 07 3149; SIDEROPHORE; TETRACYCLINE; TETRACYCLINE DERIVATIVE; UK 57562; UNCLASSIFIED DRUG; UNINDEXED DRUG; VERAPAMIL; ANTIINFECTIVE AGENT;

ANTIBIOTIC RESISTANCE; DRUG INHIBITION; DRUG MECHANISM; DRUG POTENTIATION; DRUG STRUCTURE; DRUG TRANSPORT; EFFUSION; MEMBRANE TRANSPORT; MULTIDRUG RESISTANCE; NONHUMAN; PROTEIN FUNCTION; REVIEW; STRUCTURE ACTIVITY RELATION; BACTERIUM; DRUG ANTAGONISM; DRUG EFFECT; GRAM NEGATIVE BACTERIUM; GRAM POSITIVE BACTERIUM; METABOLISM;

ANTI-BACTERIAL AGENTS; BACTERIA; CARRIER PROTEINS; GRAM-NEGATIVE BACTERIA; GRAM-POSITIVE BACTERIA;

EID: 15744392285     PISSN: 14724472     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (77)

1. Lomovskaya O, Warren MS, Lee A, Galazzo J, Fronko R, Lee M, Blais J, Cho D, Chamberland S, Renau T, Leger R 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(1):105-116. This paper describes the approach utilized for the discovery of RND efflux pump inhibitors and the initial characterization of lead compounds.
2. Ryan BM, Dougherty TJ, Belieau D, Chang J, Dougherty BA, Barrett JF: Efflux in bacteria: What do we really know about it? Expert Opin Investig Drugs (2001) 10(8):1409-1422. A good general review, including a description of past and current research on efflux pump inhibitors.
3. Van Bambeke F, Balzi E, Tulkens PM: Antibiotic efflux pumps. Biochem Pharmacol (2000) 60(4):457-470. An excellent review of antimicrobial agent efflux pumps that discusses structure, phylogeny, mechanism of action, substrate specificity issues and therapeutic implications.
4. Putman M, Van Veen HW, Konings WN: Molecular properties of bacterial multidrug transporters. Microbiol Mol Biol Rev (2000) 64(4):672-693.
5. Van Bembeke F, Glupczynski Y, Plesiat P, Pechere JC, Tulkens PM: Antibiotic efflux pumps in prokaryotic cells: Occurrence, impact on resistance and strategies for the future of antimicrobial therapy. J Antimicrob Chemother (2003) 51(5):1055-1065.
6. Lomovskaya O, Watkins WJ: Efflux pumps: Their role in antibacterial drug discovery. Curr Med Chem (2001) 8(14):1699-1711.
7. Markham PN, Neyfakh AA: Inhibition of the multidrug transporter NorA prevents emergence of norfloxacin resistance in Staphylococcus aureus. Antimicrob Agents Chemother (1996) 40(11):2673-2674.
8. Markham PN: Inhibition of the emergence of ciprofloxacin resistance in Streptococcus pneumoniae by the multidrug efflux inhibitor reserpine. Antimicrob Agents Chemother (1999)43(4):988-989.
9. Brown MH, Skurray RA: Staphylococcal multidrug efflux protein QacA. J Mol Microbiol Biotechnol (2001) 3(2):163-170.
10. Lee A, Mao W, Warren MS, Mistry A, Hoshino K, Okumura R, Ishida H, Lomovskaya O: Interplay between efflux pumps may provide either additive or multiplicative effects on drug resistance. J Bacteriol (2000) 182(11):3142-3150.
11. Srikumar R, Paul CJ, Poole K: Influence of mutations in the mexR repressor gene on expression of the MexA-MexB-OprM multidrug efflux system of Pseudomonas aeruginosa. J Bacteriol (2000) 182(5):1410-1414.
12. Kaatz GW, Seo SM, Ruble CA: Efflux-mediated fluoroquinolone resistance in Staphylococcus aureus. Antimicrob Agents Chemother (1993) 37(5):1086-1994.
13. McDonnell G, Russell AD: Antiseptics and disinfectants: Activity, action, and resistance. Clin Microbiol Rev (1999) 12(1):147-179. A comprehensive review of biocides, discussing mode of action and spectrum of activity. It also speculates whether the increased use of antiseptics and disinfectants induce antibiotic resistance.
14. Russell AD: Do biocides select for antibiotic resistance? J Pharm Pharmacol (2000) 52(2):227-233.
15. Russell AD: Introduction of biocides into clinical practice and the impact on antibiotic-resistant bacteria. J Appl Microbiol (2002) 92(Suppl):121-135.
16. Poole K: Mechanisms of bacterial biocide and antibiotic resistance. J Appl Microbiol (2002) 92(Suppl):55-64.
17. Nikaido H: Multidrug efflux pumps of Gram-negative bacteria. J Bacteriol (1996) 178(20):5853-5859.
18. Poole K: Efflux-mediated resistance to fluoroquinolones in Gram-negative bacteria. Antimicrob Agents Chemother (2000) 44(9):2233-2241.
19. Kobayashi N, Nishino K, Yamaguchi A: Novel macrolide-specific ABC-type transporter in Escherichia coli. J Bacteriol (2001) 183(19):5639-5644.
20. McMurry L, Petrucci RE, Levy SB: Active efflux of tetracycline encoded by four genetically different tetracycline resistance determinants in Escherichia coli. Proc Natl Acad Sci USA (1980) 77(7):3974-3977. This paper provides the initial description of tetracycline efflux as a relevant resistance mechanism in E coli.
21. Nikaido H, Zgurskaya HI: AcrAB and related multidrug efflux pumps of Escherichia coli. J Mol Microbiol Biotechnol (2001) 3(2):215-218.
22. Poole K: Multidrug efflux pumps and antimicrobial resistance in Pseudomonas aeruginosa and related organisms. J Mol Microbiol Biotechnol (2001) 3(2):255-264.
23. Poole K, Srikumar R: Multidrug efflux in Pseudomonas aeruginosa: Components, mechanisms and clinical significance. Curr Top Med Chem (2001)1(1):59-71. An excellent review of P aeruginosa RND drug pumps and their potential role as drug targets.
24. Chuanchuen R, Narasaki CT, Schweitzer HP: The MexJK efflux pump of Pseudomonas aeruginosa requires OprM for antibiotic efflux but not for efflux of triclosan. J Bacteriol (2002) 184(18):5036-5044.
25. Nikaido H: Multiple antibiotic resistance and efflux. Curr Opin Microbiol (1998) 1(5):516-523.
26. Nikaido H: Preventing drug access to targets: Cell surface permeability barriers and active efflux in bacteria. Semin Cell Dev Biol (2001)12(3):215-223.
27. Taylor DE, Chau A: Tetracycline resistance mediated by ribosomal protection. Antimicrob Agents Chemother (1996) 40(1):1-5.
28. Speer BS, Salyers AA: Novel tetracycline resistance gene that chemically modifies tetracycline. J Bacteriol (1989) 171 (1):148-153.
29. Nelson ML, Park BH, Andrews JS, Georgian VA, Thomas RC, Levy SB: Inhibition of the tetracycline efflux antiport protein by 13-thio-substftuted 5-hydroxy-6deoxytetracyclines. J Med Chem (1993) 36(3):370-377.
30. Nelson ML, Park BH, Levy SB: Molecular requirements for the inhibition of the tetracycline antiport protein and the effect of potent inhibitors on the growth of tetracycline-resistant bacteria. J Med Chem (1994) 37(9):1355-1361.
31. B antiport protein. Antimicrob Agents Chemother (1999) 43(7):1719-1724.
32. + antiporter of Staphylococcus aureus. FEBS Lett (1997) 412(2):337-340.
33. Silvia AM, Gavitt NE, Pere WD, Hayashi SF: Identification of a tetracycline efflux resistance reverser UK-57,562. ICAAC (1999) 39: AbS 1272.
34. Rothstein DM, McGlynn M, Bernan V, McGahren J, Zaccardi J, Cekleniak N, Bertrand KP: Detection of tetracyclines and efflux pump inhibitors. Antimicrob Agents Chemother (1993) 37(8):1624-1629.
35. Yoshida T, Muratani T, Iyobe S, Mitsuhashi S: Mechanisms of high-level resistance to fluoroquinolones in urinary tract isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother (1994) 38(7):1466-1469.
36. Chen HY, Yuan M, Livermore DM: Mechanisms of resistance to β-lactam antibiotics amongst Pseudomonas aeruginosa isolates collected in the UK in 1993. J Med Microbiol (1995) 43(4):300-309.
37. Fukuda H, Hosaka M, Iyobe S, Gotoh T, Nishino T, Hirai K: nfxC-type quinolone resistance in a clinical isolate of Pseudomonas aeruginosa. Antimicrob Agents Chemother (1995) 39(3):790-792.
38. Lomovskaya O, Lee A, Hoshino K, Ishida H, Mistry A, Warren MS, Boyer E, Chamberland S, Lee VJ: Use of a genetic approach to evaluate the consequences of inhibition of efflux pumps in Pseudomonas aeruginosa. Antimicrob Agents Chemother (1999) 43(6):1340-1346. This paper describes methodology employed to create Mex pump-deficient strains.
39. Lee MD, Galazzo JL, Staley AL, Lee JC, Warren MS, Fuernkranz H, Chamberland S, Lomovskaya O, Miller GH: Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance. Farmaco (2001) 56(1-2):81-85.
40. Lee JC, Galazzo JL, Ianiro T, Warren MS, Cano RJ, Chamberland S, Lomovskaya O, Lee MD: MF-EA-371α and MF-EA-371δ, novel bacterial efflux pump inhibitors from microbial fermentation. ICAAC (2000) 40:Abs 1499.
41. Ribera A, Ruiz J, Jimenez de Anta MT, Vila J: Effect of an efflux pump inhibitor on the MIC of nalidixic acid for Acinetobacter baumanii and Stenotrophomonas maltophilia clinical isolates. J Antimicrob Chemother (2002) 49(4):697-698.
42. Renau TE, Leger R, Flamme EM, Sangalang J, She MW, Yen R, Gannon CL, Griffith D, Chamberland S, Lomovskaya O, Hecker SJ et al: Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of the fluoroquinolone antibacterial levofloxacin. J Med Chem (1999) 42(24):4928-4931.
43. Warren MS, Lee JC, Lee A, Hoshino K, Ishida H, Lomovskaya O: An inhibitor of the Mex pumps from Pseudomonas aeruginosa is also a substrate of these pumps. ICAAC(2000) 40:Abs 1495.
44. Renau TE, Leger R, Flamme EM, She MW, Gannon CL, Mathias KM, Lomovskaya O, Chamberland S, Lee VJ, Ohta T, Nakayama K et al: Addressing the stability of C-capped dipeptide efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorg Med Chem Lett (2001) 11(5):663-667.
45. Renau TE, Leger R, Yen R, She MW, Flamme EM, Sangalang J, Gannon CL, Chamberland S, Lomovskaya O, Lee VJ: Peptidomimetics of efflux pump inhibitors potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorg Med Chem Lett (2002) 12(5):763-766.
46. Griffith D, Lomovskaya O, Lee VJ, Dudley M: Potentiation of levofloxacin by MC-02,595, a broad-spectrum efflux pump inhibitor in mouse models of infection due to Pseudomonas aeruginosa with combinations of different Mex pump expression and a gyrA mutation. ICAAC (2000) 40:Abs 1496.
47. Cho D, Lofland D, Blais J, Tangen K, Cotter D, Lomovskaya O, Chamberland S, Dudley MN: An efflux pump inhibitor, MC-04,124, enhances the activity of macrolides against Gram negative bacteria. ICAAC (2000) 40:Abs 1497.
48. Griffith DC, Corcoran E, Sorensen K, Cho D, Lomovskaya O, Dudley MN: Potentiation of levofloxacin and azithromycin by MC-04,124, a broad spectrum efflux pump inhibitor, in mouse models of infection due to strains of P aeruginosa and E coli expressing efflux pumps. ICAAC (2001) 41:Abs F-340.
49. Renau TE, Léger R, Filonova L, Flamme EM, Wang M, Yen R, Cho D, Griffith D, Chamberland S, Dudley MN, Lee VJ et al: Conformationally restricted analogs of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa. Bioorg Med Chem Lett (2003) 13(16):2755-2758.
50. Zhang JZ, Watkins WJ, Lee VJ, McMillen W, Belej P, Mathias K, Blais J, Cho D, Griffith D, Dudley MN, Ohta T et al: 2-(Aminoalkyl)benzimidazoles - a class of broad-spectrum efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa. ICAAC (2001) 41:Abs F-342.
51. Chevalier J, Atifi S, Eyraud A, Mahamoud A, Barbe J, Pages J-M: New pyridoquinoline derivatives as potential inhibitors of the fluoroquinolone efflux pump in resistant Enterobacter aerogenes strains. J Med Chem (2001) 44(23):4023-4026.
52. Paulsen IT, Brown MH, Skurray RA: Proton-dependent multidrug efflux systems. Microbiol Rev (1996) 60(4):575-608. A comprehensive review of phylogeny, and known structure and function data of secondary MDR transporters.
53. Ng EYW, Trucksis M, Hooper DC: Quinolone resistance mediated by norA: Physiologic characterization and relationship to flqB, a quinolone resistance locus on the Staphylococcus aureus chromosome. Antimicrob Agents Chemother (1994) 38(6):1345-1355.
54. Aeschlimann JR, Dresser LD, Kaatz GW, Rybak MJ: Effects of NorA inhibitors on in vitro antibacterial activities and postantibiotic effects of levofloxacin, ciprofloxacin, and norfloxacin in genetically related strains of Staphylococcus aureus. Antimicrob Agents Chemother (1999) 43(2):335-340.
55. Aeschlimann JR, Kaatz GW, Rybak MJ: The effects of NorA inhibition on the activities of levofloxacin, ciprofloxacin and norfloxacin against two genetically related strains of Staphylococcus aureus in an in vitro infection model. J Antimicrob Chemother (1999) 44(3):343-349.
56. Kaatz GW, Moudgal VV, Seo SM, Kristiansen JE: Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus. Antimicrob Agents Chemother (2003) 47(3):719-726.
57. Kaatz GW, Moudgal VV, Seo SM, Bondo-Hansen J, Kristiansen JE: Phenylpiperidine selective serotonin reuptake inhibitors interfere with multidrug efflux pump activity in Staphylococcus aureus. Int J Antimicrob Agents (2003) 22(3):254-261.
58. Sridhar KS, Krishnan A, Samy TS, Sauerteig A, Wellham LL, McPhee G, Duncan RC, Anac SY, Ardalan B, Benedetto PW: Prochlorperazine as a doxorubicin-efflux blocker: Phase I clinical and pharmacokinetic studies. Cancer Chemother Pharmacol (1993) 31(6):423-430.
59. Sridhar KS, Krishnan A, Samy TS, Duncan RC, Sauerteig A, McPhee GV, Auguste ME, Benedetto PW: Phase I and pharmacokinetics studies of prochlorperazine 2-h iv infusion as a doxorubicin-efflux blocker. Cancer Chemother Pharmacol (1994) 34(5):377-384.
60. Hiemke C, Hartter S: Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther (2000) 85(1):11-28.
61. Hyafil F, Vergely C, Du Vignaud P, Grand-Perret T: In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. Cancer Res (1993) 53(19):4595-4602.
62. Gibbons S, Oluwatuyi M, Kaatz GW: A novel inhibitor of multidrug efflux pumps in Staphylococcus aureus. J Antimicrob Chemother (2003)51(1):13-17.
63. Markham PN, Westhaus E, Klyatchko K, Johnson ME, Neyfakh AA: Multiple novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus. Antimicrob Agents Chemother (1999) 43(10):2404-2408. This paper describes the approach employed for the discovery and initial evaluation of several promising inhibitors of the S aureus NorA multidrug efflux pump.
64. Stermitz FR, Lorenz P, Tawara JN, Zenewicz LA, Lewis K: Synergy in a medicinal plant: Antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci USA (2000) 97(4):1433-1437.
65. Guz NR, Stermitz FR: Synthesis and structures of regioisomeric hydnocarpin-type flavonolignans. J Nat Prod (2000) 63(8):1140-1145.
66. Guz NR, Stermitz FR, Johnson JB, Beeson TD, Willen S, Hsiang J, Lewis K: Flavonolignan and flavone inhibitors of a Staphylococcus aureus multidrug resistance pump: Structure-activity relationships. J Med Chem (2001) 44(2):261-268.
67. Stermitz FR, Scriven LN, Tegos G, Lewis K: Two flavonols from Artemisa annua which potentiate the activity of berberine and norfloxacin against a resistant strain of Staphylococcus aureus. Planta Med (2002) 68(12):1140-1141.
68. Van Veen HW, Venema K, Bolhuis H, Oussenko I, Kok J, Poolman B, Dreissen AJ, Konings WN: Drug transport mediated by a bacterial homologue of the human multidrug transporter MDR1. Proc Natl Acad Sci USA (1996) 93(20):10668-10672.
69. Ross JI, Eady EA, Cove JH, Cunliffe WJ, Baumberg S, Wooton JC: Inducible erythromycin resistance in staphylococci is encoded by a member of the ATP-binding transport super-gene family. Mol Microbiol (1990) 4(7):1207-1214.
70. Morita Y, Kodama K, Shiota S, Mine T, Kataoka A, Mizushima T, Tsuchiya T: NorM, a putative multidrug efflux protein, of Vibrio parahaemolyticus and its homolog in Escherichia coli. Antimicrob Agents Chemother (1998) 42(7):1778-1782.
71. Miyamae S, Ueda O, Yoshimura F, Hwang J, Tanaka Y, Nikaido H: A MATE family multidrug efflux transporter pumps out fluoroquinolones in Bacteroides thetaiotaomicron. Antimicrob Agents Chemother (2001) 45(12):3341-3346.
72. Ubukata K, Itoh-Yamashita N, Konno M: Cloning and expression of the norA gene for fluoroquinolone resistance in Staphylococcus aureus. Antimicrob Agents Chemother (1989) 33(9):1535-1539. This paper provides the first description of NorA and describes the mechanism of fluoroquinolone resistance in S aureus.
73. Neyfakh AA, Bidnenko VE, Chen LB: Efflux-mediated multidrug resistance in Bacillus subtilis: Similarities and dissimilarities with the mammalian system. Proc Natl Acad Sci USA (1991) 88(11):4781-4785. This paper describes the initial characterization of Bmr, including its sequence, substrate specificity and sensitivity to inhibitors such as verapamil and reserpine.
74. Bolhuis H, Poelarends G, Van Veen HW, Poolman B, Driessen AJ, Konings WN: The lactococcal ImrP gene encodes a proton motive force-dependent drug transporter. J Biol Chem (1995) 270(44):26092-26098.
75. Gill MJ, Brenwald NP, Wise R: Identification of an efflux pump gene, pmrA, associated with fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother (1999) 43(1):187-189. This paper provides the first description of the multidrug efflux pump PmrA and determines whether it is responsible for efflux-mediated resistance in S pneumoniae.
76. Littlejohn TG, Diberardino D, Messerotti LJ, Spiers SJ, Skurray RA: Structure and evolution of a family of genes encoding antiseptic and disinfectant resistance in Staphylococcus aureus. Gene (1991) 101(1):59-66.
77. Arkin IT, Russ WP, Lebendiker M, Schuldiner S: Determining the secondary structure and orientation of EmrE, a multi-drug transporter, indicates a transmembrane four-helix bundle. Biochemistry (1996) 35(22):7233-7238.