Anti-mutagenic agent targeting LexA to combat antimicrobial resistance in mycobacteria

• Published in: The Journal of biological chemistry Vol. 300; no. 9; p. 107650
• Main Authors: Chatterjee, Chitral, Mohan, Gokul Raj, Chinnasamy, Hariharan V., Biswas, Bhumika, Sundaram, Vidya, Srivastava, Ashutosh, Matheshwaran, Saravanan
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.09.2024; American Society for Biochemistry and Molecular Biology
• Subjects: antimicrobial resistance (AMR); LexA; Mycobacterium tuberculosis; small molecule inhibitor; SOS response; transcription; Mycobacterium tuberculosis; transcription; LexA; AMR; antimicrobial resistance (AMR); MD; SOS response; Mtb; TB; small molecule inhibitor
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1016/j.jbc.2024.107650

Antimicrobial resistance (AMR) is a serious global threat demanding innovations for effective control of pathogens. The bacterial SOS response, regulated by the master regulators, LexA and RecA, contributes to AMR through advantageous mutations. Targeting the LexA/RecA system with a novel inhibitor could suppress the SOS response and potentially reduce the occurrence of AMR. RecA presents a challenge as a therapeutic target due to its conserved structure and function across species, including humans. Conversely, LexA which is absent in eukaryotes, can be potentially targeted, due to its involvement in SOS response which is majorly responsible for adaptive mutagenesis and AMR. Our studies combining bioinformatic, biochemical, biophysical, molecular, and cell-based assays present a unique inhibitor of mycobacterial LexA, wherein we show that the inhibitor interacts directly with the catalytic site residues of LexA of Mycobacterium tuberculosis (Mtb), consequently hindering its cleavage, suppressing SOS response thereby reducing mutation frequency and AMR.