Coupling of Peptidoglycan Synthesis to Central Metabolism in Mycobacteria: Post-transcriptional Control of CwlM by Aconitase

ABSTRACT: Summary Mycobacterium tuberculosis causes human tuberculosis, and a better understanding of its biology is required to identify vulnerabilities that might be exploited in developing new therapeutics. The iron-sulfur cluster of the essential M. tuberculosis central metabolic enzyme, aconitase (AcnA), disassembles when exposed to oxidative/nitrosative stress or iron chelators. The catalytically inactive apo-AcnA interacts with a sequence resembling an iron-responsive element (IRE) located within the transcript of another essential protein, CwlM, a regulator of peptidoglycan synthesis. A Mycobacterium smegmatis cwlM conditional mutant complemented with M. tuberculosis cwlM with a disrupted IRE is unable to recover from combinations of oxidative, nitrosative, and iron starvation stresses. An equivalent M. tuberculosis cwlM conditional mutant complemented with the cwlM gene lacking a functional IRE exhibits a growth defect in THP-1 macrophages. It appears that AcnA acts to couple peptidoglycan synthesis and central metabolism, and disruption of this coupling potentially leaves mycobacteria vulnerable to attack by macrophages. Graphical Abstract Highlights • Mutation of the M. tuberculosis cwlM IRE impairs binding by apo-aconitase• Apo-aconitase:cwlM IRE interactions couple metabolism and peptidoglycan synthesis• Decoupling by mutation of the cwlM IRE sensitizes M. smegmatis to host-related stresses• Mutation of the cwlM IRE in M. tuberculosis results in a growth defect in macrophages Bancroft et al. show that host-associated stresses cause disassembly of the iron-sulfur cluster of Mycobacterium tuberculosis aconitase. The resulting apo-aconitase binds an IRE-like sequence within the cwlM transcript. Disruption of this interaction enhances the sensitivity of mycobacteria to iron starvation and nitrosative and oxidative stresses and impairs growth in macrophages.

SUBMITTER: Bancroft P 

PROVIDER: S-EPMC7527780 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature