Relation between bacterial efflux pump and antibiotic resistance

Abstract

Abstract: Drug resistance in bacteria has attracted much attention in clinical antibacterial therapy for years. In addition to the well known mechanisms, such as inactivation of drugs and alteration of targets, drug extruding pumps also play a major role in resistance to antibacterials. Efflux pumps are widespread in bacteria and have broad variety of substrates. Their presence contributes both intrinsic and acquired bacterial resistance. Efflux-mediated drug-resistance has been recognized as the major mechanism of resistance to antibacterial agents in Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. The impact of antibiotic efflux pumps on therapy must be taken fully into account for the selection of antimicrobials. The design of specific, potent inhibitors appears to be an important goal for the improved control of infectious diseases in the near future. An alternative approach is to develop antibacterials that would bypass the action of efflux pumps. This paper will review recent progress on the role of bacterial efflux transporters in antibiotic resistance from the aspects of classification, structure, regulation and the inhibitors, which will provide references for the further investigation.

Key words: Efflux pump, Bacteria, Antibiotics, Drug resistance

CLC Number:

R978.1

SUN Yuan, ZHA Wei-bin, ZHOU Fang, WU Xiao-lan, ZHANG Jing-wei, WANG Guang-ji. Relation between bacterial efflux pump and antibiotic resistance[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2012, 17(5): 593-600.

References

[1] de Lencastre H, Oliveira D, Tomasz A. Antibiotic resistant Staphylococcus aureus: a paradigm of adaptive power[J]. Curr Opin Microbiol,2007,10(5):428-435.
[2] 李乃静, 李岩, 潘作东, 等. 生物被膜肺炎克雷伯杆菌AmpC酶、超广谱β-内酰胺酶的检测[J]. 中国临床药理学与治疗学, 2008, 13(4): 384-387.
[3] Ball PR, Chopra I, Eccles SJ. Accumulation of tetracyclines by Escherichia coli K-12[J]. Biochem Biophys Res Commun,1977,77(4):1500-1507.
[4] Li XZ, Nikaido H. Efflux-mediated drug resistance in bacteria[J]. Drugs,2004,64(2):159-204.
[5] Law CJ, Maloney PC, Wang DN. Ins and outs of major facilitator superfamily antiporters[J]. Annu Rev Microbiol,2008,62:289-305.
[6] Kuroda T, Tsuchiya T. Multidrug efflux transporters in the MATE family[J]. Biochim Biophys Acta,2009,1794(5):763-768.
[7] Bay DC, Rommens KL, Turner RJ. Small multidrug resistance proteins: a multidrug transporter family that continues to grow[J]. Biochim Biophys Acta,2008,1778(9):1814-1838.
[8] Li XZ, Nikaido H. Efflux-mediated drug resistance in bacteria: an update[J]. Drugs,2009,69(12):1555-1623.
[9] Seeger MA, Diederichs K, Eicher T, et al. The AcrB efflux pump: conformational cycling and peristalsis lead to multidrug resistance[J]. Curr Drug Targets,2008,9(9):729-749.
[10] Nishino K, Yamaguchi A. Analysis of a complete library of putative drug transporter genes in Escherichia coli[J]. J Bacteriol,2001,183(20):5803-5812.
[11] Kobayashi N, Nishino K, Yamaguchi A. Novel macrolide-specific ABC-type efflux transporter in Escherichia coli[J]. J Bacteriol,2001,183(19):5639-5644.
[12] Sugimura M, Maseda H, Hanaki H, et al. Macrolide antibiotic-mediated downregulation of MexAB-OprM efflux pump expression in Pseudomonas aeruginosa[J]. Antimicrob Agents Chemother,2008,52(11):4141-4144.
[13] Chen S, Cui S, McDermott PF, et al. Contribution of target gene mutations and efflux to decreased susceptibility of Salmonella enterica serovar typhimurium to fluoroquinolones and other antimicrobials[J]. Antimicrob Agents Chemother,2007,51(2):535-542.
[14] Akiba M, Lin J, Barton YW, et al. Interaction of CmeABC and CmeDEF in conferring antimicrobial resistance and maintaining cell viability in Campylobacter jejuni[J]. J Antimicrob Chemother,2006,57(1):52-60.
[15] Truong-Bolduc QC, Hooper DC. The transcriptional regulators NorG and MgrA modulate resistance to both quinolones and beta-lactams in Staphylococcus aureus[J]. J Bacteriol,2007,189(8):2996-3005.
[16] Narui K, Noguchi N, Wakasugi K, et al. Cloning and characterization of a novel chromosomal drug efflux gene in Staphylococcus aureus[J]. Biol Pharm Bull,2002,25(12):1533-1536.
[17] Garvey MI, Piddock LJ. The efflux pump inhibitor reserpine selects multidrug-resistant Streptococcus pneumoniae strains that overexpress the ABC transporters PatA and PatB[J]. Antimicrob Agents Chemother,2008,52(5):1677-1685.
[18] Mata MT, Baquero F, Perez-Diaz JC. A multidrug efflux transporter in Listeria monocytogenes[J]. FEMS Microbiol Lett,2000,187(2):185-188.
[19] Ramos JL, Martinez-Bueno M, Molina-Henares AJ, et al. The TetR family of transcriptional repressors[J]. Microbiol Mol Biol Rev,2005,69(2):326-356.
[20] Andresen C, Jalal S, Aili D, et al. Critical biophysical properties in the Pseudomonas aeruginosa efflux gene regulator MexR are targeted by mutations conferring multidrug resistance[J]. Protein Sci,2010,19(4):680-692.
[21] Chen H, Hu J, Chen PR, et al. The Pseudomonas aeruginosa multidrug efflux regulator MexR uses an oxidation-sensing mechanism[J]. Proc Natl Acad Sci U S A,2008,105(36):13586-13591.
[22] Daigle DM, Cao L, Fraud S, et al. Protein modulator of multidrug efflux gene expression in Pseudomonas aeruginosa[J]. J Bacteriol,2007,189(15):5441-5451.
[23] Morita Y, Cao L, Gould VC, et al. nalD encodes a second repressor of the mexAB-oprM multidrug efflux operon of Pseudomonas aeruginosa[J]. J Bacteriol,2006,188(24):8649-8654.
[24] Morero NR, Monti MR, Argarana CE. Effect of ciprofloxacin concentration on the frequency and nature of resistant mutants selected from Pseudomonas aeruginosa mutS and mutT hypermutators[J]. Antimicrob Agents Chemother,2011,55(8):3668-3676.
[25] Fetar H, Gilmour C, Klinoski R, et al. mexEF-oprN multidrug efflux operon of Pseudomonas aeruginosa: regulation by the MexT activator in response to nitrosative stress and chloramphenicol[J]. Antimicrob Agents Chemother,2011,55(2):508-514.
[26] Stock AM, Robinson VL, Goudreau PN. Two-component signal transduction[J]. Annu Rev Biochem,2000,69:183-215.
[27] Eguchi Y, Oshima T, Mori H, et al. Transcriptional regulation of drug efflux genes by EvgAS, a two-component system in Escherichia coli[J]. Microbiology,2003,149(Pt 10):2819-2828.
[28] Nishino K, Honda T, Yamaguchi A. Genome-wide analyses of Escherichia coli gene expression responsive to the BaeSR two-component regulatory system[J]. J Bacteriol,2005,187(5):1763-1772.
[29] Tavio MM, Aquili VD, Poveda JB, et al. Quorum-sensing regulator sdiA and marA overexpression is involved in in vitro-selected multidrug resistance of Escherichia coli[J]. J Antimicrob Chemother,2010,65(6):1178-1186.
[30] De la Cruz MA, Calva E. The complexities of porin genetic regulation[J]. J Mol Microbiol Biotechnol,2010,18(1):24-36.
[31] Lee JH, Lee KL, Yeo WS, et al. SoxRS-mediated lipopolysaccharide modification enhances resistance against multiple drugs in Escherichia coli[J]. J Bacteriol,2009,191(13):4441-4450.
[32] Feuerriegel S, Heisig P. Role of global regulator Rma for multidrug efflux-mediated fluoroquinolone resistance in Salmonella[J]. Microb Drug Resist,2008,14(4):259-263.
[33] Truong-Bolduc QC, Ding Y, Hooper DC. Posttranslational modification influences the effects of MgrA on norA expression in Staphylococcus aureus[J]. J Bacteriol,2008,190(22):7375-7381.
[34] Jonsson IM, Lindholm C, Luong TT, et al. mgrA regulates staphylococcal virulence important for induction and progression of septic arthritis and sepsis[J]. Microbes Infect,2008,10(12/13):1229-1235.
[35] Lomovskaya O, Bostian KA. Practical applications and feasibility of efflux pump inhibitors in the clinic--a vision for applied use[J]. Biochem Pharmacol,2006,71(7):910-918.
[36] Zechini B, Versace I. Inhibitors of multidrug resistant efflux systems in bacteria[J]. Recent Pat Antiinfect Drug Discov,2009,4(1):37-50.
[37] Askoura M, Mottawea W, Abujamel T, et al. Efflux pump inhibitors (EPIs) as new antimicrobial agents against Pseudomonas aeruginosa[J]. Libyan J Med,2011,6.
[38] Leitner I, Nemeth J, Feurstein T, et al. The third-generation P-glycoprotein inhibitor tariquidar may overcome bacterial multidrug resistance by increasing intracellular drug concentration[J]. J Antimicrob Chemother,2011,66(4):834-839.
[39] Mirza ZM, Kumar A, Kalia NP, et al. Piperine as an inhibitor of the MdeA efflux pump of Staphylococcus aureus[J]. J Med Microbiol,2011,60(Pt 10):1472-1478.
[40] Kern WV, Steinke P, Schumacher A, et al. Effect of 1-(1-naphthylmethyl)-piperazine, a novel putative efflux pump inhibitor, on antimicrobial drug susceptibility in clinical isolates of Escherichia coli[J]. J Antimicrob Chemother,2006,57(2):339-343.
[41] Liu J, Keelan P, Bennett PM, et al. Characterization of a novel macrolide efflux gene, mef(B), found linked to sul3 in porcine Escherichia coli[J]. J Antimicrob Chemother,2009,63(3):423-426.
[42] Lin HT, Bavro VN, Barrera NP, et al. MacB ABC transporter is a dimer whose ATPase activity and macrolide-binding capacity are regulated by the membrane fusion protein MacA[J]. J Biol Chem,2009,284(2):1145-1154.
[43] Li XZ, Poole K, Nikaido H. Contributions of MexAB-OprM and an EmrE homolog to intrinsic resistance of Pseudomonas aeruginosa to aminoglycosides and dyes[J]. Antimicrob Agents Chemother,2003,47(1):27-33.
[44] Nishino K, Latifi T, Groisman EA. Virulence and drug resistance roles of multidrug efflux systems of Salmonella enterica serovar Typhimurium[J]. Mol Microbiol,2006,59(1):126-141.
[45] Bialek-Davenet S, Marcon E, Leflon-Guibout V, et al. In vitro selection of ramR and soxR mutants overexpressing efflux systems by fluoroquinolones as well as cefoxitin in Klebsiella pneumoniae[J]. Antimicrob Agents Chemother,2011,55(6):2795-2802.
[46] Xu XJ, Su XZ, Morita Y, et al. Molecular cloning and characterization of the HmrM multidrug efflux pump from Haemophilus influenzae Rd[J]. Microbiol Immunol,2003,47(12):937-943.
[47] Wang Y, Wu CM, Lu LM, et al. Macrolide-lincosamide-resistant phenotypes and genotypes of Staphylococcus aureus isolated from bovine clinical mastitis[J]. Vet Microbiol,2008,130(1/2):118-125.
[48] Davis DR, McAlpine JB, Pazoles CJ, et al. Enterococcus faecalis multi-drug resistance transporters: application for antibiotic discovery[J]. J Mol Microbiol Biotechnol,2001,3(2):179-184.
[49] Choudhuri BS, Bhakta S, Barik R, et al. Overexpression and functional characterization of an ABC (ATP-binding cassette) transporter encoded by the genes drrA and drrB of Mycobacterium tuberculosis[J]. Biochem J,2002,367(Pt 1):279-285.
[50] Danilchanka O, Mailaender C, Niederweis M. Identification of a novel multidrug efflux pump of Mycobacterium tuberculosis[J]. Antimicrob Agents Chemother,2008,52(7):2503-2511.
[51] Singh M, Jadaun GP, Ramdas, et al. Effect of efflux pump inhibitors on drug susceptibility of ofloxacin resistant Mycobacterium tuberculosis isolates[J]. Indian J Med Res,2011,133(5):535-540.
[52] DeMarco CE, Cushing LA, Frempong-Manso E, et al. Efflux-related resistance to norfloxacin, dyes, and biocides in bloodstream isolates of Staphylococcus aureus[J]. Antimicrob Agents Chemother,2007,51(9):3235-3239.
[53] Hannula M, Hanninen ML. Effect of putative efflux pump inhibitors and inducers on the antimicrobial susceptibility of Campylobacter jejuni and Campylobacter coli[J]. J Med Microbiol,2008,57(Pt 7):851-855.
[54] Stavri M, Piddock LJ, Gibbons S. Bacterial efflux pump inhibitors from natural sources[J]. J Antimicrob Chemother,2007,59(6):1247-1260.
[55] Sharma S, Kumar M, Nargotra A, et al. Piperine as an inhibitor of Rv1258c, a putative multidrug efflux pump of Mycobacterium tuberculosis[J]. J Antimicrob Chemother,2010,65(8):1694-1701.