Autophagy: A new strategy for host-directed therapy of tuberculosis

Paik, Seungwha; Kim, Jin‐Kyung; Chung, Chaeuk; Jo, Eun-Kyeong

doi:10.1080/21505594.2018.1536598

Cited by 123 publications

(128 citation statements)

References 105 publications

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“…These observations are in concordance with previous reports showing that induction of autophagy can be harnessed as a host-directed therapy (HDT) either alone or in combination with first-line TB drugs (Dara et al, 2019). Despite identification of autophagy inducers, enough information is not available about the cooperative action of various known or unknown mechanisms regulated by autophagy (Paik et al, 2019). Therefore, evaluation of promising autophagy inducers as host-directed therapy either alone or in combination with first-line TB drugs will refine therapeutic interventions against TB.…”

Section: Discussionsupporting

confidence: 90%

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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Section: Discussionsupporting

confidence: 90%

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

et al. 2020

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“…Host-directed therapies have emerged as a promising alternative to counter TB. Drugs targeting host defense mechanisms or processes such as vesicle trafficking can assist the host in responding appropriately to Mtb infection, thereby promoting the effectiveness of drug treatments and reducing the time required for treatment (4,5). Using an in vivo model for the early stages of TB disease we have demonstrated the importance of Dram1 for the elimination of intracellular mycobacteria and the cell fate of infected macrophages.…”

Section: Discussionmentioning

confidence: 98%

Deficiency in the autophagy modulator Dram1 exacerbates pyroptotic cell death of Mycobacteria-infected macrophages

Zhang

Varela

Forn-Cuní

et al. 2019

Preprint

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AbstractDNA Damage Regulated Autophagy Modulator 1 (DRAM1) is a stress-inducible regulator of autophagy and cell death. DRAM1 has been implicated in cancer, myocardial infarction, and infectious diseases, but the molecular and cellular functions of this transmembrane protein remain poorly understood. Previously, we have proposed DRAM1 as a host resistance factor for tuberculosis (TB) and a potential target for host-directed anti-infective therapies. In this study, we generated a zebrafish dram1 mutant and investigated its loss-of-function effects during Mycobacterium marinum (Mm) infection, a widely used model in TB research. In agreement with previous knockdown analysis, dram1 mutation increased the susceptibility of zebrafish larvae to Mm infection. RNA sequencing revealed major effects of Dram1 deficiency on metabolic, immune response, and cell death pathways during Mm infection, whereas only minor effects on proteinase and metabolic pathways were found under uninfected conditions. Furthermore, unchallenged dram1 mutants did not display overt autophagic defects, but autophagic targeting of Mm was reduced in absence of Dram1. The phagocytic ability of macrophages in dram1 mutants was unaffected, but acidification of Mm-containing vesicles was strongly reduced, indicating that Dram1 is required for phagosome maturation. By in vivo imaging we observed that Dram1-deficient macrophages fail to restrict Mm during early stages of infection. The resulting increase in bacterial burden could be reverted by knockdown of inflammatory caspase a (caspa) and gasdermin Eb (gsdmeb), demonstrating pyroptosis as the mechanism underlying premature cell death of Mm-infected macrophages in dram1 mutants. Collectively, these data demonstrate that dissemination of mycobacterial infection in zebrafish larvae is promoted in absence of Dram1 due to reduced maturation of mycobacteria-containing vesicles, failed intracellular containment, and consequent pyroptotic cell death of infected macrophages. These results provide new evidence that Dram1 plays a central role in host resistance to intracellular infection, acting at the crossroad of autophagy and cell death.

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“…Mtb pathogenicity is closely related to its ability to survive in macrophages through the deployment of strategies to escape or neutralize host defenses [1]. One of these defenses is autophagy, a cellular process that allows for the capture of intracellular bacteria and their killing by lysosomes [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, damage to the phagosomal membrane, which is triggered by the Type VII secretion system Esx-1, promotes xenophagy via the exposure of pathogen-associated molecular patterns (PAMPs) to the cytosolic sensor cGAS (cyclic GMP-AMP synthase), followed by STING signaling and the ubiquitination of damaged phagosome or via galectin recruitment onto the damaged phagosome [7,[13][14][15]. Alternatively, the xenophagy of Mtb-containing phagosomes can be achieved exogenously using pharmaceutical drugs or immunomodulators, such as cytokines [5,16]. Xenophagy requires the formation of an LC3-decorated double-membrane-bound compartment, which is called an autophagosome and engulfs the bacteria.…”

Section: Introductionmentioning

confidence: 99%

The Lipid Virulence Factors of Mycobacterium tuberculosis Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages

Bah

Sanicas

Nigou

et al. 2020

Cells

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Autophagy is an important innate immune defense mechanism that controls Mycobacterium tuberculosis (Mtb) growth inside macrophages. Autophagy machinery targets Mtb-containing phagosomes via xenophagy after damage to the phagosomal membrane due to the Type VII secretion system Esx-1 or via LC3-associated phagocytosis without phagosomal damage. Conversely, Mtb restricts autophagy-related pathways via the production of various bacterial protein factors. Although bacterial lipids are known to play strategic functions in Mtb pathogenesis, their role in autophagy manipulation remains largely unexplored. Here, we report that the lipid virulence factors sulfoglycolipids (SLs) and phthiocerol dimycocerosates (DIMs) control autophagy-related pathways through distinct mechanisms in human macrophages. Using knock-out and knock-in mutants of Mtb and Mycobacterium bovis BCG (Bacille Calmette Guerin) and purified lipids, we found that (i) Mtb mutants with DIM and SL deficiencies promoted functional autophagy via an MyD88-dependent and phagosomal damage-independent pathway in human macrophages; (ii) SLs limited this pathway by acting as TLR2 antagonists; (iii) DIMs prevented phagosomal damage-independent autophagy while promoting Esx-1-dependent xenophagy; (iv) and DIMs, but not SLs, limited the acidification of LC3-positive Mtb compartments. In total, our study reveals an unexpected and intricate role for Mtb lipid virulence factors in controlling autophagy-related pathways in human macrophages, thus providing further insight into the autophagy manipulation tactics deployed by intracellular bacterial pathogens.

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Autophagy: A new strategy for host-directed therapy of tuberculosis

Cited by 123 publications

References 105 publications

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

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

Deficiency in the autophagy modulator Dram1 exacerbates pyroptotic cell death of Mycobacteria-infected macrophages

The Lipid Virulence Factors of Mycobacterium tuberculosis Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages

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