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bioRxiv · 10.1101/2022.05.06.490884

Understanding the role of c-di-AMP signaling in determining antibiotic tolerance in Mycobacterium smegmatis: generation of resistant mutants and regrowth of persisters

Pal, A. K.·Ghosh, A.
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Abstract

In this study, we probe the role of secondary messenger c-di-AMP in drug tolerance, which includes both persister and resistant mutant characterization of Mycobacterium smegmatis. Specifically, with the use of c-di-AMP null and overproducing mutants, we showed how c-di-AMP plays a significant role in resistance mutagenesis against antibiotics with different mechanisms of action. We elucidated the specific molecular mechanism linking the elevated intracellular c-di-AMP level and high mutant generation and highlighted the significance of non-homology-based DNA repair. Further investigation enabled us to identify the unique mutational landscape of target and non-target mutation categories linked to intracellular c-di-AMP levels. Overall fitness cost of unique target mutations was estimated in different strain backgrounds, and then we showed the critical role of c-di-AMP in driving epistatic interactions between resistance genes, resulting in the evolution of multi-drug tolerance. Finally, we identified the role of c-di-AMP in persister cells regrowth and mutant enrichment upon cessation of antibiotic treatment.

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Pal, A. K., Ghosh, A.. 2022-05-06. Understanding the role of c-di-AMP signaling in determining antibiotic tolerance in Mycobacterium smegmatis: generation of resistant mutants and regrowth of persisters. https://doi.org/10.1101/2022.05.06.490884

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