Small Molecule Efflux Pump Inhibitors in Mycobacterium tuberculosis: A Rational Drug Design Perspective

Mini Reviews in Medicinal Chemistry
Erika KappSamantha L Sampson

Abstract

Drug resistance in Mycobacterium tuberculosis (M. tuberculosis) complicates management of tuberculosis. Efflux pumps contribute to low level resistance and acquisition of additional high level resistance mutations through sub-therapeutic concentrations of intracellular antimycobacterials. Various efflux pump inhibitors (EPIs) have been described for M. tuberculosis but little is known regarding the mechanism of efflux inhibition. As knowledge relating to the mechanism of action and drug target is central to the rational drug design of safe and sufficiently selective EPIs, this review aims to examine recent developments in the study of EPIs in M. tuberculosis from a rational drug development perspective and to provide an overview to facilitate systematic development of therapeutically effective EPIs. Review of literature points to a reduction in cellular energy or direct binding to the efflux pump as likely mechanisms for most EPIs described for M. tuberculosis. This review demonstrates that, where a direct interaction with efflux pumps is expected, both molecular structure and general physicochemical properties should be considered to accurately predict efflux pump substrates and inhibitors. Non-competitive EPIs do not necessar...Continue Reading

Citations

Jul 19, 2018·Frontiers in Microbiology·Diana MachadoMarco Pieroni
Oct 23, 2020·Indian Journal of Microbiology·Josenildo Cândido de OliveiraFillipe de Oliveira Pereira
Apr 8, 2021·Applied Biochemistry and Biotechnology·Santasree Sarma BiswasJayanti Datta Roy
May 9, 2021·European Journal of Pharmacology·Vaibhav ThakurVinod Tiwari
Jun 24, 2021·Journal of Bioenergetics and Biomembranes·Cristina Rodrigues Dos Santos BarbosaFrancisco Assis Bezerra da Cunha
Jul 10, 2021·Advances in Pharmacological and Pharmaceutical Sciences·Erika KappSarel F Malan
Sep 29, 2021·Chemical Biology & Drug Design·Ashley King, Meghan S Blackledge

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