Repurposing antimalarials for the treatment of NTM infections

点击翻译按钮获取中文摘要

Abstract The prevalence of pulmonary nontuberculous mycobacterial (NTM) infections caused by Mycobacterium abscessus complex (MABSC) and Mycobacterium avium complex (MAC) species is increasing worldwide and poses a particular threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis, chronic obstructive pulmonary disease and bronchiectasis. The intrinsic recalcitrance of these pathogens to chemotherapeutic treatments and alarming treatment failure rates place a high priority on the development of more effective treatment approaches. The ability of MABSC and MAC to persist intracellularly and extracellularly within granulomatous lesions in a non-replicating state is likely to contribute to the drug tolerance of these microorganisms and to treatment failure in chronically-infected individuals. Further compounding this problem is the ability of MABSC and MAC to form what appears to be genetically programmed biofilms during human pulmonary infections. A common stress faced by intra- and extracellular NTM inside activated immune cells, in avascular necrotic and caseous regions of granulomas, and within microaggregates or biofilms is the inhibition of aerobic respiration caused by O2 depletion or exposure to nitric oxide (NO) and carbon monoxide. M. tuberculosis (Mtb) is known to survive this stress by inducing a regulon of ~50 genes that drives the entry of the bacterium in a non-replicating state while adapting its metabolism to maintain energy levels and a redox balance compatible with survival in the absence of respiration. Accordingly, inhibitors of the regulator which controls the expression of this regulon are actively being sought for their potential to shorten tuberculosis treatment and lower relapse rates when used in combination with standard-of-care antibiotics. Our recent studies indicate that the orthologous regulators of MABSC and MAC play a similar function as in Mtb. Genetic and pharmacological disruption of this regulator in MABSC led to inhibition of biofilm formation in addition to decreasing bacterial viability and reversing drug tolerance under hypoxia. Most importantly, two inhibitors of this regulator in MABSC which we identified showed significant bactericidal activity in MABSC-infected mice in addition to potentiating the activity of standard-of-care antibiotics used in combination. Since these two inhibitors are either clinically-used or in phase II clinical trial, they offer repurposing opportunities that could be a short route to the clinic. These exciting findings stimulated the submission of this grant application in which we propose to thoroughly decipher the mechanisms underlying the therapeutic and adjunct therapeutic benefits of these inhibitors in MABSC (Aim 1) and to determine whether the same therapeutic strategy may be applied to MAC (Aim 2).