Abstract
Over the last years, nontuberculous mycobacteria (NTM) have emerged as important human pathogens. Infections caused by NTM are often difficult to treat due to an intrinsic multidrug resistance for the presence of a lipid-rich outer membrane, thus encouraging an urgent need for the development of new drugs for the treatment of mycobacterial infections. Efflux pumps (EPs) are important elements that are involved in drug resistance by preventing intracellular accumulation of antibiotics. A promising strategy to decrease drug resistance is the inhibition of EP activity by EP inhibitors (EPIs), compounds that are able to increase the intracellular concentration of antimicrobials. Recently, attention has been focused on identifying EPIs in mycobacteria that could be used in combination with drugs. The aim of the present review is to provide an overview of the current knowledge on EPs and EPIs in NTM and also, the effect of potential EPIs as well as their combined use with antimycobacterial drugs in various NTM species are described.
Highlights
Infections by nontuberculous mycobacteria (NTM) represent a relevant problem for human health in many countries in the world
The aim of the present review is to provide an overview of the current knowledge on Efflux pumps (EPs) and EP inhibitors (EPIs) in NTM and describe the effect of potential EPIs as well as their combined use with antimycobacterial drugs in various NTM species
Tap protein from M. fortuitum uses the electrochemical gradient across the cytoplasmic membrane to extrude tetracycline from the cell; this efflux activity is inhibited by carbonyl cyanide m-chlorophenylhydrazone (CCCP) and RES, consistent with the decrease in MIC observed in antibiotic susceptibility testing in the presence of these inhibitors
Summary
Infections by nontuberculous mycobacteria (NTM) represent a relevant problem for human health in many countries in the world. Over the last years, NTM have emerged as important human pathogens and infections caused by these organisms have increased globally [3,4,5]. Some examples of EPIs in M. tuberculosis include the following compounds: the Ca2+ channel blocker verapamil (VP), which decreased the level of resistance to rifampicin, isoniazid, ofloxacin, streptomycin and to the new anti-TB drugs bedaquiline and clofazimine; phenothiazines, such as thioridazine (TZ) and chlorpromazine (CPZ), which have been proven to reduce clarithromycin and isoniazid resistance in M. tuberculosis complex; protonophores, including carbonyl cyanide m-chlorophenylhydrazone (CCCP) and 2,4-dinitrophenol (DNP), which decreased the level of resistance to rifampicin, isoniazid, ofloxacin, and streptomycin; valinomycin, which acts reducing the gradient generated by K+ and inhibits novobiocin and rifampin resistance mediated by the P55 pump; plant-derived EPI, such as reserpine (RES), which has been shown to influence the level of resistance to numerous anti-TB drugs, and piperine (PIP), which is found to be synergistic with rifampicin treatment in a mouse infection model of M. tuberculosis [29,30]. The following paragraphs will consider the studies carried out on each species of NTM
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