Kapp Erika, Malan Sarel F, Joubert Jacques, Sampson Samantha L
University of the Western Cape, School of Pharmacy Bellville, Bellville, South Africa.
University of Stellenbosh, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences Bellville, Bellville, Western Cape, South Africa.
Mini Rev Med Chem. 2018;18(1):72-86. doi: 10.2174/1389557517666170510105506.
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 necessarily demonstrate the same requirements as competitive inhibitors and it is therefore essential to differentiate between competitive and non-competitive inhibition to accurately determine structure activity relationships for efflux pump inhibition. It is also evident that there are various similarities between inhibitors of prokaryotic and eukaryotic efflux pumps but, depending on the specific chemical scaffolds under investigation, it may be possible to design EPIs that are less prone to inhibition of human P-glycoprotein, thereby reducing side effects and drug-drug interactions.
结核分枝杆菌（M. tuberculosis）中的耐药性使结核病的治疗变得复杂。外排泵导致低水平耐药，并通过细胞内抗分枝杆菌药物的亚治疗浓度获得额外的高水平耐药突变。已经描述了多种针对结核分枝杆菌的外排泵抑制剂（EPI），但关于外排抑制机制知之甚少。由于与作用机制和药物靶点相关的知识是安全且具有足够选择性的EPI合理药物设计的核心，本综述旨在从合理药物开发的角度审视结核分枝杆菌EPI研究的最新进展，并提供概述以促进治疗有效EPI的系统开发。文献综述指出，细胞能量的减少或与外排泵的直接结合是大多数已描述的结核分枝杆菌EPI的可能机制。本综述表明，在预期与外排泵有直接相互作用的情况下，应同时考虑分子结构和一般物理化学性质，以准确预测外排泵底物和抑制剂。非竞争性EPI不一定表现出与竞争性抑制剂相同的要求，因此区分竞争性和非竞争性抑制对于准确确定外排泵抑制的构效关系至关重要。同样明显的是，原核和真核外排泵抑制剂之间存在各种相似之处，但根据所研究的特定化学支架，有可能设计出不太容易抑制人P-糖蛋白的EPI，从而减少副作用和药物-药物相互作用。
