Iron limitation in M. tuberculosis has broad impact on bacterial metabolism revealing alternative routes to novel therapeutics
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ABSTRACT:
PROVIDER: PRJNA807360 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18042650_1.fastq.gz | Fastqsanger.gz | |||
| SRR18042650_2.fastq.gz | Fastqsanger.gz | |||
| SRR18042651_1.fastq.gz | Fastqsanger.gz | |||
| SRR18042651_2.fastq.gz | Fastqsanger.gz | |||
| SRR18042652_1.fastq.gz | Fastqsanger.gz |
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Project description:Mycobacterium tuberculosis (Mtb), the cause of the human pulmonary disease tuberculosis (TB), contributes to approximately 1.5 million deaths every year. Prior work has established that lipids serve as the primary carbon and energy source for Mtb in vivo and fulfill major roles in Mtb physiology and pathogenesis. We conducted a high-throughput screen to identify novel inhibitors of Mtb survival in its host macrophage. One of the hit compounds identified in this screen, sAEL057, demonstrated highest activity on Mtb grown in conditions where cholesterol was the primary carbon source. Transcriptional and functional data indicate that sAEL057 limits Mtb’s access to iron by acting as an iron chelator. Furthermore, pharmacological and genetic inhibition of iron acquisition led to dysregulation of cholesterol catabolism, revealing a previously unappreciated linkage between these pathways. These results identify a vulnerability in Mtb’s metabolic programming and physiology that could be targeted for therapeutic purposes.
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Project description:Mycobacterium tuberculosis (Mtb), the cause of the human pulmonary disease tuberculosis (TB), contributes to approximately 1.5 million deaths every year. Prior work has established that lipids are actively catabolized by Mtb in vivo and fulfill major roles in Mtb physiology and pathogenesis. We conducted a high-throughput screen to identify inhibitors of Mtb survival in its host macrophage. One of the hit compounds identified in this screen, sAEL057, demonstrates highest activity on Mtb growth in conditions where cholesterol was the primary carbon source. Transcriptional and functional data indicate that sAEL057 limits Mtb's access to iron by acting as an iron chelator. Furthermore, pharmacological and genetic inhibition of iron acquisition results in dysregulation of cholesterol catabolism, revealing a previously unappreciated linkage between these pathways. Characterization of sAEL057's mode of action argues that Mtb's metabolic regulation reveals vulnerabilities in those pathways that impact central carbon metabolism.
| S-EPMC9271047 | biostudies-literature