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.

Exposure to nitric oxide drives transition to differential culturability inMycobacterium tuberculosis

“…The up-regulation of murI, coding for glutamate racemase [46], cwlM [47], and pbpA [48] suggested that remodeling of peptidoglycan was involved in the transition to Rpf-dependency. Indeed, expression of cwlM was previously shown to be upregulated by treatment with spermine NONOate [49]. Consistent with the observation that ND-treatment resulted in Rpf-dependent mycobacteria, three rpf genes were down-regulated (rpfA, rpfB and rpfE; 9.5-, 3.9-and 33.2-fold, respectively).…”

Genome-wide peptidoglycan profiling of Vibrio cholerae

“…For instance, almost 98% of the mutants of the V. cholerae transposon library present a statistically significant alteration of their PG profile (deviate at least 1SD from the average), and more than the 50% of the mutants presented a variation higher than 2SD of the average of the whole library for at least one muropeptide or a PG-feature) that included loci from all COG categories. These results are in agreement with studies that linked the cell wall with seemingly unrelated pathways/processes (e.g.,(Bancroft et al, 2020; Campbell et al, 2021; Masser et al, 2021)). Conversely, certain mutants in cell wall-annotated genes did not show an altered PG profile suggesting the existence of functional redundancies or condition-specific activities.…”

The Role of Phosphorylation and Acylation in the Regulation of Drug Resistance in Mycobacterium tuberculosis

“…CwlM is a peptidoglycan hydrolase (amidase) that is responsible for the hydrolysis of bacterial cell walls [ 42 ]. Together with UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), the enzyme involved in the first step of the synthesis of peptidoglycan, CwlM regulates the biosynthesis of peptidoglycan [ 42 , 43 , 44 ]. PknB can activate the overexpression of MurA and cell division by phosphorylating CwlM under a rich nutritional environment for MTB growth.…”