Abstract
The increasing incident rates of drug-resistant tuberculosis (DR-TB) is a global health concern and has been further complicated by the emergence of extensive and total drug-resistant strains. Identification of new chemical entities which are compatible with first-line TB drugs, possess activity against DR-, and metabolically less active bacteria is required to tackle this epidemic. Here, we have performed phenotypic screening of a small molecule library against Mycobacterium bovis BCG and identified 24 scaffolds that exhibited MIC99 values of at least 2.5 μM. The most potent small molecule identified in our study was a nitroso containing pyrazole derivative, NSC 18725. We observed a significant reduction in viable bacilli load of starved Mycobacterium tuberculosis upon exposure to NSC 18725. The action of NSC 18725 was “synergistic” with isoniazid (INH) and “additive” with other drugs in our checkerboard assays. Structure-activity relationship (SAR) studies of the parent compound revealed that pyrazole derivatives without a functional group at fourth position lacked anti-mycobacterial activity in vitro. The derivative with para-chlorophenyl substitution at the first position of the pyrazole ring was the most active scaffold. We also demonstrate that NSC 18725 is able to induce autophagy in differentiated THP-1 macrophages. The induction of autophagy by NSC 18725 is the major mechanism for the killing of intracellular slow and fast-growing mycobacteria. Taken together, these observations support the identification of NSC 18725 as an antimycobacterial compound, which synergizes with INH, is active against non-replicative mycobacteria and induces autophagy in macrophages.
Highlights
Tuberculosis (TB), is responsible for the highest number of annual deaths among the infectious diseases (Glaziou et al, 2018)
The culturing of various mycobacterial strains was carried out in Middlebrook (MB) 7H9 medium supplemented with 0.2% glycerol, 1 × Albumin-Dextrose-Saline (ADS), 0.05% Tween-80, or 7H11 agar supplemented with 1 × Oleic acid-AlbuminDextrose-Saline (OADS) as previously described (Singh et al, 2013)
Several reports have shown that modulation of autophagy by small molecules results in faster clearance of intracellular M. tuberculosis, we further evaluated the antimicrobial efficacy of NSC 18725 against the pathogen replicating inside macrophages (Kidwai et al, 2017; Mawatwal et al, 2017; Dhiman and Singh, 2018)
Summary
Tuberculosis (TB), is responsible for the highest number of annual deaths among the infectious diseases (Glaziou et al, 2018). The. Mechanism of Action of NSC18725 Against M. tuberculosis current regimen for TB treatment comprises of an intensive phase of 2 months of administration of isoniazid (INH), rifampicin (RIF), ethambutol (EMB), and pyrazinamide (PZA) followed by a 4-month continuation phase for INH and RIF administration (Snider and Roper, 1992; Bass et al, 1994). Mechanism of Action of NSC18725 Against M. tuberculosis current regimen for TB treatment comprises of an intensive phase of 2 months of administration of isoniazid (INH), rifampicin (RIF), ethambutol (EMB), and pyrazinamide (PZA) followed by a 4-month continuation phase for INH and RIF administration (Snider and Roper, 1992; Bass et al, 1994) Several factors, such as poor patient compliance, low tolerability, and sub-optimal drug concentration contribute to the emergence of drug resistant (DR-) strains. The new candidate drug should (i) target a novel metabolic pathway, (ii) possess activity against DR-strains and metabolically dormant bacteria, and (iii) be compatible with current first-line TB and anti-retroviral therapy
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