Efflux Pump Inhibitors: New Hope in Microbial Multidrug Resistance
Role of Efflux Pump Inhibitors in multidrug resistance protein (P-gp)
DOI:
https://doi.org/10.54844/cai.2022.0077Keywords:
permeation glycoprotein, multidrug resistance, efflux pump, anti-microbialAbstract
From the last some decades, microbial multidrug resistance (MDR) has developed one of the big treats in the many drug therapy. Due to this effect, so many sectors were get affected including the pharmaceutical sector, animal husbandry sector as well as in some way the agriculture sector too. There are so many mechanisms were developed by the microbes to developed resistance towards the medicines consisting of the development of degrading enzymes, structural modification in the microbes which is responsible to bind the drug, as well as last but not the least developing many effluxes pumps to push drug molecules outside of the microbial cell. Many studies demonstrated that lots of antibiotics and anticancer agents are majorly get affected by efflux pumps present on the cell wall. These mechanisms are observed in many common microbes including gram-positive and gram-negative microbes. As a result, efflux pumps are to be taken on top priority for the minimization of multidrug resistance. Up to date lots of work is done regarding the permeation glycoprotein (P-gp) efflux pump inhibition but still, there is a need to explore some more innovative approaches towards MDR. In this current perspective, we have discussed the key points related to pre-existing and future prospects in this regard.
References
Spreacker PJ, Thomas NE, Beeninga WF, Brousseau M, Hibbs KM, Henzler-Wildman KA. A new substrate triggers susceptibility by uncoupling a bacterial multidrug resistance efflux pump. bioRxiv 2021. (Preprint)
Wright GD. Antibiotics: a new hope. Chem Biol 2012;19:3–10.
Katrajkar K, Darji L, Kethavath D, Thakkar S, Kshirsagar B, Misra M. Shedding light on interaction of so called inactive ingredients (excipients) with permeability-glycoprotein. J Drug Deliv Sci Technol 2019;52:531–552.
Davin-Regli A, Pages JM, Ferrand A. Clinical Status of Efflux Resistance Mechanisms in Gram-Negative Bacteria. Antibiotics (Basel) 2021;10:1117
Seukep AJ, Fokoua-Maxime CD, Mbuntcha HG, Chen G, Assob JCN,Tenniswood M, et al. Bacterial Drug Efflux Pump Inhibitors from Plants, in Antimicrobial Resistance 2022. Springer, Singapore.2022:487–532.
Tegos GP, Haynes M, Strouse JJ, Khan MM, Bologa CG, Oprea TI, Sklar LA. Microbial efflux pump inhibition: tactics and strategies. Curr Pharm De 2011;17:1291–1302.
Ebbensgaard AE, Løbner-Olesen A, Frimodt-Møller J. The Role of Efflux Pumps in the Transition from Low-Level to Clinical Antibiotic Resistance. Antibiotics (Basel) 2020;9:855.
Thakur V, Uniyal A, Tiwari V. A comprehensive review on pharmacology of efflux pumps and their inhibitors in antibiotic resistance.
Eur J Pharmacol 2021;903:174151.
Putnam, D. Exploitation of P-glycoprotein Over-expression for Targeted Drug Delivery to Breast Cancer 2011. https://apps.dtic.mil/
sti/citations/ADA571769. Accessed on February 20, 2022.
Zhou SF. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 2008;38:802–
Mizutani T, Masuda M, Nakai E, Furumiya K, Togawa H, Nakamura Y, et al. Genuine functions of P-glycoprotein (ABCB1). Curr Drug
Metab 2008;9:167–174.
Li Y, Yuan H, Yang K, Xu W, Tang W, Li X. The structure and functions of P-glycoprotein. Curr Med Chem 2010;17:786–800. 13. Johnstone RW, Ruefli AA, Smyth MJ. Multiple physiological functions for multidrug transporter P-glycoprotein? Trends Biochem Sci
;25:1–6.
Dewanjee S, Dua TK, Bhattacharjee N, Das A, Gangopadhyay M, Khanra R, et al. Natural Products as Alternative Choices for P-Glycoprotein (P-gp) Inhibition. Molecules 2017;22:871.
Georgantzopoulou A, Skoczyńska E, Van den Berg JH, Brand W, Legay S, Klein SG, et al. P-gp efflux pump inhibition potential of
common environmental contaminants determined in vitro. Environ Toxicol Chem 2014;33:804–813.
Rathi E, Kumar A, Kini SG. Computational approaches in efflux pump inhibitors: current status and prospects. Drug Discov Today
;25:1883–1890.
Sharma A, Gupta VK, Pathania R. Efflux pump inhibitors for bacterial pathogens: From bench to bedside. Indian J Med Res
;149:129–145.
Monteiro KLC, de Aquino TM, Mendonça Junior FJB. An Update on Staphylococcus aureus NorA Efflux Pump Inhibitors. Curr Top
Med Chem 2020;20:2168–2185.
Seukep AJ, Kuete V, Nahar L, Sarker SD, Guo M. Plant-derived secondary metabolites as the main source of efflux pump inhibitors
and methods for identification. J Pharm Anal 2020;10:277–290.
Choudhury D, Talukdar AD, Chetia P, Bhattacharjee A, Choudhury MD. Screening of Natural Products and Derivatives for the Identification of RND Efflux Pump Inhibitors. Comb Chem High Throughput Screen 2016;19:705–713.
Seukep AJ, Kuete V, Nahar L, Sarker SD, Guo M. Plant-derived secondary metabolites as the main source of efflux pump inhibitors
and methods for identification. J Pharm Anal 2020;10:277–290.
Stavri M, Piddock LJ, Gibbons S. Bacterial efflux pump inhibitors from natural sources. J Antimicrob Chemother 2007;59:1247-60.
AlMatar M, Albarri O, Makky EA, Köksal F. Efflux pump inhibitors: new updates. Pharmacol Rep 2021 Feb;73:1–16.
Durães F, Pinto M, Sousa E. Medicinal Chemistry Updates on Bacterial Efflux Pump Modulators. Curr Med Chem 2018;25:6030–
Wang Y, Venter H, Ma S. Efflux Pump Inhibitors: A Novel Approach to Combat Efflux-Mediated Drug Resistance in Bacteria. Curr Drug Targets 2016;17:702–219.
Samreen, Ahmad I, Qais FA, Maheshwari M, Rumbaugh KR. Efflux Pump Inhibitors and Their Role in the Reversal of Drug Resistance. Antibacterial Drug Discovery to Combat MDR. Springer, Singapore. 2019:251–275.
Kumar M, Singh K, Naran K, Hamzabegovic F, Hoft DF, Warner DF, et al. Design, Synthesis, and Evaluation of Novel Hybrid Efflux
Pump Inhibitors for Use against Mycobacterium tuberculosis. ACS Infect Dis 2016;2:714–725.
Gupta D, Singh A, Khan AU. Nanoparticles as Efflux Pump and Biofilm Inhibitor to Rejuvenate Bactericidal Effect of Conventional
Antibiotics. Nanoscale Res Lett 2017;12:454.
Handzlik J, Matys A, Kieć-Kononowicz K. Recent Advances in Multi-Drug Resistance (MDR) Efflux Pump Inhibitors of Gram-Positive Bacteria S. aureus. Antibiotics (Basel) 2013;2:28–45.
Vila J, Martí S, Sánchez-Céspedes J. Porins, efflux pumps and multidrug resistance in Acinetobacter baumannii. J Antimicrob
Chemother 2007;59:1210–1215.
Opperman TJ, Nguyen ST. Recent advances toward a molecular mechanism of efflux pump inhibition. Front Microbiol 2015;6:421.
Zechini B, Versace I. Inhibitors of multidrug resistant efflux systems in bacteria. Recent Pat Antiinfect Drug Discov 2009;4:37–50.
Schindler BD, Jacinto P, Kaatz GW. Inhibition of drug efflux pumps in Staphylococcus aureus: current status of potentiating existing
antibiotics. Future Microbiol 2013;8:491–507.
Ruggerone P, Murakami S, Pos KM, Vargiu AV. RND efflux pumps: structural information translated into function and inhibition mechanisms. Curr Top Med Chem 2013;13:3079–100.
Sun J, Deng Z, Yan A. Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations. Biochem
Biophys Res Commun 2014 Oct 17;453:254–267.
Nikaido H, Takatsuka Y. Mechanisms of RND multidrug efflux pumps. Biochim Biophys Acta 2009;1794:769–781.
Mahamoud A, Chevalier J, Alibert-Franco S, Kern WV, Pagès JM. Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy. J Antimicrob Chemother 2007;59:1223–1229.
Ernst R, Kueppers P, Stindt J, Kuchler K, Schmitt L. Multidrug efflux pumps: substrate selection in ATP-binding cassette multidrug efflux pumps--first come, first served? FEBS J 2010;277:540–549.
Ahire ED, Sonawane VN, Surana KR, Talele S. Drug Discovery, Drug-Likeness Screening, and Bioavailability: Development of
Drug-Likeness Rule for Natural Products. Apple Academic Press 2021;191–208.
Askoura M, Mottawea W, Abujamel T, Taher I. Efflux pump inhibitors (EPIs) as new antimicrobial agents against Pseudomonas
aeruginosa. Libyan J Med 2011;13:6.
Lamut A, Peterlin Mašič L, Kikelj D, Tomašič T. Efflux pump inhibitors of clinically relevant multidrug resistant bacteria. Med Res Rev
;39:2460–2504.
Song L, Wu X. Development of efflux pump inhibitors in antituberculosis therapy. Int J Antimicrob Agents 2016;47:421–429.
Lomovskaya O, Watkins W. Inhibition of efflux pumps as a novel approach to combat drug resistance in bacteria. J Mol Microbiol
Biotechnol 2001;3:225–236.
Downloads
Published
How to Cite
Issue
Section
Downloads
License
Copyright (c) 2022 Eknath D. Ahire, Sanjay J. Kshirsagar
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
