MtrAB two-component system is crucial for the intrinsic resistance and virulence of Mycobacterium abscessus

• Published in: International journal of antimicrobial agents 2025-01, p.107442, Article 107442
• Main Authors: Zhang, Jingran, Ju, Yanan, Li, Lijie, Hameed, H.M. Adnan, Yusuf, Buhari, Gao, Yamin, Fang, Cuiting, Tian, Xirong, Ding, Jie, Ma, Wanli, Chen, Xinwen, Wang, Shuai, Zhang, Tianyu
• Format: Article
• Language: English
• Subjects: cell division; intrinsic resistance; Mycobacterium abscessus; two-component system MtrAB; virulence
• ISSN: 0924-8579
• DOI: 10.1016/j.ijantimicag.2024.107442

•Knockout of mtrA, mtrB or mtrAB leads to increased sensitivity of M. abscessus in vitro and in vivo.•The mtrA, mtrB or mtrAB knockout M. abscessus strains exhibit highly reduced virulence.•MtrA and MtrB are potential targets for anti-M. abscessus drug discovery.•Knockout of mtrA, mtrB or mtrAB results in defective cell division in M. abscessus. Mycobacterium abscessus (Mab) poses serious therapeutic challenges, largely due to its intrinsic resistance to many antibiotics. The development of targeted therapeutic strategies necessitates the identification of bacterial factors that contribute to its reduced susceptibility to antibiotics and/or to the killing by its host cells. In this study, we discovered that Mab strains with disrupted mtrA, mtrB or both, or a gene-edited mtrA encoding MtrA with Tyr102Cys mutation, exhibited highly increased sensitivity to various drugs compared to the wild-type Mab. In a murine model, three antibiotics inactive against the wild-type Mab demonstrated efficacy against the mtrA and mtrB knockout strains, significantly reducing pulmonary bacterial burdens compared to untreated controls. Notably, the virulence of all the mtrA, mtrB and mtrAB knockout mutants was highly diminished, evidenced by a reduced bacterial load in mouse lungs, undetectable level in spleens, and defective growth in macrophage RAW264.7. Morphological analysis revealed elongated cell length and multiple septa in knockout strains, suggesting both MtrA and MtrB regulate cell division of Mab. Furthermore, the absence of mtrA, mtrB or both significantly increased cell envelope permeability and reduced biofilm formation. Transcriptome sequencing showed altered expression levels of multiple genes related to plasma membrane, fatty acid metabolism and biosynthesis pathways in wild-type Mab and mtrA knockout strain. In summary, this study suggests that MtrA and MtrB play a crucial role in the intrinsic resistance and virulence of Mab by affecting cell division and altering cell permeability. Consequently, MtrA and MtrB represent promising targets for the discovery of anti-Mab drugs. [Display omitted]