Efflux Pumps of Mycobacterium tuberculosis play a significant role in anti

TLDR: In this paper, the authors have shown that four efflux pumps of Mycobacterium tuberculosis play a vital role in mediating efflux of 48 different chemical scaffolds, and that inhibitors of one or several of these pumps could have a significant impact in the treatment for tuberculosis.

Abstract: 31 32 Active efflux of drugs mediated by efflux pumps which confer drug resistance is one of 33 the mechanisms developed by bacteria to counter the adverse effects of antibiotics and 34 chemicals. To understand these efflux mechanisms in Mycobacterium tuberculosis, we 35 generated knock-out (KO) mutants of four efflux pumps of this pathogen, belonging to 36 different classes. We measured the minimal inhibitory concentrations (MICs) and kill 37 values of two different compound classes on the wild-type (WT) and the efflux pump 38 (EP) KO mutants in the presence and absence of the efflux inhibitors verapamil and L39 phenylalanyl-L-arginyl-β-naphthylamide (PAβN). Among the pumps studied, the efflux 40 pumps belonging to the ABC (ATP-binding cassette) class, encoded by Rv1218c and the 41 SMR (small multidrug resistance) class, encoded by Rv3065 appear to play important 42 roles in mediating efflux of different chemical classes and antibiotics. Efflux pumps 43 encoded by Rv0849 and Rv1258c also mediate efflux of these compounds but to lesser 44 extent. Increased kill is observed in WT M. tuberculosis cells by these compounds in the 45 presence of either verapamil or PAβN. The efflux pump KO mutants were more 46 susceptible to these compounds in the presence of efflux inhibitors. We have shown 47 that these four efflux pumps of M. tuberculosis play a vital role in mediating efflux of 48 different chemical scaffolds. Inhibitors of one or several of these efflux pumps could 49 have a significant impact in the treatment for tuberculosis. 50 Identification and characterization of Rv0849, a new efflux pump belonging 51 to the MFS (major facilitator superfamily) class is reported. 52