Clionamines stimulate autophagy, inhibit Mycobacterium tuberculosis survival in macrophages, and target Pik1

Persaud, Rosanne; Li, Sheena C.; Chao, Joseph D.; Forestieri, Roberto; Donohue, Elizabeth; Balgi, Aruna D.; Zheng, Xingji; Chao, Jesse T.; Yashiroda, Yoko; Yoshimura, Mami; Loewen, Christopher; Gingras, Anne‐Claude; Boone, Charles; Roberge, Michel; Andersen, Raymond J.

doi:10.1016/j.chembiol.2021.07.017

Cited by 12 publications

(14 citation statements)

References 80 publications

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“…BRI affects cell membrane organization, the CWI pathway and calcium metabolism in S. cerevisiae. As an additional tool to investigate BRI MoA, we performed several screens using haploid null (ScWG), temperature-sensitive (TS), overexpression (MoBY), and heterozygous (haploinsufficiency profiling, HET) strain libraries of the model yeast S. cerevisiae 22,58 . Pooled cultures of barcoded S. cerevisiae strains from these collections were grown in liquid YPGal medium for 19 to 28 h at 26 or 30 o C (Figure 3a).…”

Section: Resultsmentioning

confidence: 99%

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Brilacidin, a novel antifungal agent againstCryptococcus neoformans

Diehl,

Pinzan,

de Castro

et al. 2024

Preprint

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Cryptococcus neoformanscauses cryptococcosis, one of the most prevalent fungal diseases, generally characterized by meningitis. There is a limited and not very effective number of drugs available to combat this disease. In this manuscript, we show the host defense peptide mimetic brilacidin (BRI) as a promising antifungal drug againstC. neoformans. BRI is able to affect the organization of the cell membrane, increasing fungal cell permeability. We also investigated the effects of BRI against the model systemSaccharomyces cerevisiaeby analyzing libraries of mutants grown in the presence of BRI. InS. cerevisiae, BRI also affects the cell membrane organization, but in addition the cell wall integrity pathway and calcium metabolism. In vivo experiments show BRI significantly reducesC. neoformanssurvival inside macrophages and partially clearsC. neoformanslung infection in an immunocompetent murine model of invasive pulmonary cryptococcosis. We also observed that BRI interacts with caspofungin (CAS) and amphotericin (AmB), potentiating their mechanism of action againstC. neoformans. BRI+CAS affects endocytic movement, calcineurin, and mitogen activated protein kinases. Our results indicate that BRI is a novel antifungal drug against cryptococcosis.

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Section: Resultsmentioning

confidence: 99%

“…Pooled yeast mutant libraries were treated with BRI. Basically, the workflow including culture, DNA extraction, and PCR amplification of each strain-specific barcode proceeded as described in 58 .…”

Section: Culture Conditions and Ergosterol Extractionmentioning

confidence: 99%

Brilacidin, a novel antifungal agent againstCryptococcus neoformans

Diehl,

Pinzan,

de Castro

et al. 2024

Preprint

Self Cite

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“…90 Various drugs, including isoniazid and pyrazinamide (first-line tuberculosis drugs) and other compounds and plants mentioned in previous studies, have been reported to target and activate host autophagy. 91,92 Recent studies have shown a variety of old remedies to be remarkably effective in warding off infections, including clonamine, 91 the antidepressant drug amoxapine, 93 and so on. Berbamine (BBM), an FDA-approved drug, inhibits drug-sensitive and resistant Mtb growth by promoting macrophage autophagy.…”

Section: Therapeutic Strategies Targeting Host Autophagymentioning

confidence: 99%

“…New therapies to manipulate host autophagy using a variety of autophagy‐inducing compounds have shown a recent trend 90 . Various drugs, including isoniazid and pyrazinamide (first‐line tuberculosis drugs) and other compounds and plants mentioned in previous studies, have been reported to target and activate host autophagy 91,92 …”

Section: Autophagymentioning

confidence: 99%

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Host‐pathogen dialogues in different cell death modes during Mycobacterium tuberculosis infection

Ruan,

Lyu,

Lai

et al. 2024

Interdisciplinary Medicine

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Tuberculosis (TB) is a fatal infectious disease that continues to pose a serious public health threat. The emergence of drug‐resistant TB has further worsened the burden of the disease. The interaction between the host and the pathogen involves multiple modes of cell death, which play a role in determining immune outcomes. Several studies have established a strong correlation between cell death and TB progression. This review explores the molecular mechanisms of various cell death modes in Mycobacterium tuberculosis (Mtb) infection and how Mtb's virulence effectors regulate these pathways, including apoptosis, autophagy, pyroptosis, ferroptosis, and necrosis. Furthermore, therapeutic strategies targeting cell death pathways have shown promising results in TB treatment. Importantly, this review highlights the significant potential of mitochondria in mediating communication between different cell death modes and influencing the final outcomes. Overall, this work provides a comprehensive summary of the role of cell death in host immune responses and immune evasion by Mtb. It also offers valuable insights into the pathogenesis of TB and immune evasion strategies employed by Mtb and contributes to the development of more effective anti‐TB therapies.

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