Calcimycin mediates mycobacterial killing by inducing intracellular calcium-regulated autophagy in a P2RX7 dependent manner

Mawatwal, Shradha; Behura, Assirbad; Ghosh, Abhirupa; Kidwai, Saqib; Mishra, Abtar; Deep, Amar; Agarwal, Sakshi; Saha, Sudipto; Singh, Ramandeep; Dhiman, Rohan

doi:10.1016/j.bbagen.2017.09.010

Cited by 30 publications

(21 citation statements)

References 58 publications

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“…However, both C7522 and D2926 showed cytotoxicity on THP-1 macrophages at a concentration higher than 2.5 M and 0.5 M, respectively. Recently, we reported that pretreatment of macrophages with calcimycin induces interleukin-12 (IL-12) production and also enhances autophagy in a P2XR7-dependent manner (22,23). In concordance with our findings, it has been reported that diphenyleneiodonium chloride displays bactericidal activity against Staphylococcus aureus and M. tuberculosis (24).…”

Section: Resultssupporting

confidence: 91%

“…Macrophage experiments. The THP-1 human monocyte cell line was maintained in RPMI 1640 medium containing 10% fetal bovine serum per standard protocols (22). THP-1 monocytes were differentiated by the addition of 20 ng/ml phorbol 12-myristate 13-acetate (PMA) for 48 h. Postdifferentiation, THP-1 cells were washed twice with 1ϫ PBS and rested for 1 day in RPMI medium.…”

Section: Methodsmentioning

confidence: 99%

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NU-6027 Inhibits Growth of Mycobacterium tuberculosis by Targeting Protein Kinase D and Protein Kinase G

Kidwai

Bouzeyen

Chakraborti

et al. 2019

Antimicrob Agents Chemother

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Tuberculosis (TB) is a global health concern, and this situation has further worsened due to the emergence of drug-resistant strains and the failure of BCG vaccine to impart protection. There is an imperative need to develop highly sensitive, specific diagnostic tools, novel therapeutics, and vaccines for the eradication of TB. In the present study, a chemical screen of a pharmacologically active compound library was performed to identify antimycobacterial compounds. The phenotypic screen identified a few novel small-molecule inhibitors, including NU-6027, a known CDK-2 inhibitor. We demonstrate that NU-6027 inhibits Mycobacterium bovis BCG growth in vitro and also displayed cross-reactivity with Mycobacterium tuberculosis protein kinase D (PknD) and protein kinase G (PknG). Comparative structural and sequence analysis along with docking simulation suggest that the unique binding site stereochemistry of PknG and PknD accommodates NU-6027 more favorably than other M. tuberculosis Ser/Thr protein kinases. Further, we also show that NU-6027 treatment induces the expression of proapoptotic genes in macrophages. Finally, we demonstrate that NU-6027 inhibits M. tuberculosis growth in both macrophage and mouse tissues. Taken together, these results indicate that NU-6027 can be optimized further for the development of antimycobacterial agents.

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Section: Resultssupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

NU-6027 Inhibits Growth of Mycobacterium tuberculosis by Targeting Protein Kinase D and Protein Kinase G

Kidwai

Bouzeyen

Chakraborti

et al. 2019

Antimicrob Agents Chemother

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“…These observations indicate that NSC 18725 induces autophagy in human macrophages. Several reports have shown that modulation of autophagy by small molecules results in faster clearance of intracellular M. tuberculosis, therefore, we further evaluated the antimicrobial efficacy of NSC 18725 against the pathogen replicating inside macrophages Mawatwal et al, 2017;Dhiman and Singh, 2018). In concordance with previous studies, we observed that autophagy induction upon NSC 18725 treatment inhibited the growth of mycobacteria in human macrophages.…”

Section: Figure 4 | (A)supporting

confidence: 85%

“…Autophagy is a lysosomal degradative process and can be used by the macrophages to inhibit growth of intracellular M. tuberculosis (Lowrie and Andrew, 1988;Bah and Vergne, 2017). Several studies have shown that small molecules inducing autophagy are able to clear intracellular DR-and DS-TB Mawatwal et al, 2017;Dhiman and Singh, 2018).…”

Section: Nsc 18725 Induces Autophagy In Differentiated Thp-1 Macrophamentioning

confidence: 99%

NSC 18725, a Pyrazole Derivative Inhibits Growth of Intracellular Mycobacterium tuberculosis by Induction of Autophagy

et al. 2020

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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 MIC 99 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 fastgrowing 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.

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“…In the same study, it has been demonstrated that metformin interferes with mitochondrial respiratory chain, induces the production of reactive oxygen species that results in killing of intracellular bacteria . In addition to metformin, several other small molecules such as nitazoxanide, geftinib, vitamin D, mTOR inhibitors, statins, verapamil, fluoxetine, carbamazepine, calcimycin, 5‐Nitro, 1–10, phenanthroline, and valproic acid inhibits growth of intracellular bacteria by inducing autophagy . Doxycycline inhibits secretion of matrix metalloproteinases, which results in reduced lung tissue damage and M. tuberculosis growth in guinea pigs .…”

Section: Host‐directed Therapiesmentioning

confidence: 99%

Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

Dhiman

Singh

2018

IUBMB Life

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Tuberculosis (TB) is a leading cause of mortality and morbidity with an estimated 1.7 billion people latently infected with the pathogen worldwide. Clinically, TB infection presents itself as an asymptomatic infection, which gradually manifests to life threatening disease. The emergence of various drug resistant strains of Mycobacterium tuberculosis and lengthy duration of chemotherapy are major challenges in the field of TB drug development. Hence, there is an urgent need to develop scaffolds that possess a novel mechanism of action, can shorten the duration of therapy, and are active against both drug resistant and susceptible strains. In this review, we will discuss recent progress made in the field of TB drug development with emphasis on screening methods and drug targets from M. tuberculosis. The current review provides insights into mechanism of action of new scaffolds that are being evaluated in various stages of clinical trials. © 2018 IUBMB Life, 70(9):905-916, 2018.

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Calcimycin mediates mycobacterial killing by inducing intracellular calcium-regulated autophagy in a P2RX7 dependent manner

Cited by 30 publications

References 58 publications

NU-6027 Inhibits Growth of Mycobacterium tuberculosis by Targeting Protein Kinase D and Protein Kinase G

NU-6027 Inhibits Growth of Mycobacterium tuberculosis by Targeting Protein Kinase D and Protein Kinase G

NSC 18725, a Pyrazole Derivative Inhibits Growth of Intracellular Mycobacterium tuberculosis by Induction of Autophagy

Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

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