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靶向 LexA 的抗诱变剂，以对抗分枝杆菌中的抗菌药物耐药性。

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

机构信息

Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, India.

Department of Biological Sciences and Engineering, Indian Institute of Technology, Gandhinagar, Gujarat, India.

出版信息

J Biol Chem. 2024 Sep;300(9):107650. doi: 10.1016/j.jbc.2024.107650. Epub 2024 Aug 8.

DOI:10.1016/j.jbc.2024.107650
PMID:39122002
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11408154/
Abstract

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.

摘要

抗微生物药物耐药性（AMR）是一个严重的全球威胁，需要创新来有效控制病原体。细菌 SOS 反应受主调控因子 LexA 和 RecA 调控，通过有利突变促进 AMR。用新型抑制剂靶向 LexA/RecA 系统可以抑制 SOS 反应，并可能减少 AMR 的发生。RecA 作为一个治疗靶点具有挑战性，因为它在包括人类在内的物种中具有保守的结构和功能。相反，LexA 在真核生物中不存在，由于其参与 SOS 反应，SOS 反应主要负责适应性突变和 AMR，因此可以作为潜在的靶点。我们的研究结合了生物信息学、生物化学、生物物理学、分子和基于细胞的测定方法，提出了一种新型的分枝杆菌 LexA 抑制剂，我们的研究表明该抑制剂直接与结核分枝杆菌（Mtb）LexA 的催化位点残基相互作用，从而抑制其切割，抑制 SOS 反应，从而降低突变频率和 AMR。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/e05a19b3f392/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/6a06d0f85e60/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/c1ae605236a6/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/d15be962a355/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/8d8e62e7623a/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/e56b03b8cb2d/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/5ea2591c01b4/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/e05a19b3f392/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/6a06d0f85e60/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/c1ae605236a6/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/d15be962a355/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/8d8e62e7623a/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/e56b03b8cb2d/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/5ea2591c01b4/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2640/11408154/e05a19b3f392/gr7.jpg

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