MRL-494 是一种抗菌剂，是 BamA 的一种抗外排和外膜渗透屏障的小分子抑制剂。MRL-494 可抑制革兰氏阳性细菌 (金黄色葡萄球菌 COL 的 MIC 值为 12.5 μM) 和革兰氏阴性细菌 (大肠杆菌 JCM158 的 MIC 值为 25 μM)。
MRL-494 is an antibacterial agent and is a small-molecule inhibitor of β-barrel assembly machine A (BamA) impervious to efflux and the outer membrane permeability barrier. MRL-494 can inhibits Gram-positive (MIC of 12.5 μM for Staphylococcus aureus COL) and Gram-negative (MIC of 25 μM for E. coli JCM158) bacterias[1][2].
The mutant protein has both altered conformation and activity, suggesting it could either inhibit MRL-494 binding or allow BamA to function in the presence of MRL-494. By cellular thermal shift assay (CETSA), MRL-494 stabilizes BamA and BamAE470K from thermally induced aggregation, indicating direct or proximal binding to both BamA and BamAE470K. It is the altered activity of BamAE470K responsible for resistance to MRL-494. MRL-494 possesses a second mechanism of action that kills gram-positive organisms. In microbes lacking an OM, MRL-494 lethally disrupts the cytoplasmic membrane. The compound cannot disrupt the cytoplasmic membrane of gram-negative bacteria because it cannot penetrate the OM. Instead, MRL-494 inhibits OMP biogenesis from outside the OM by targeting BamA[1].MRL-494 exhibits strong anti-microbial properties against both Gram-positive and Gram-negative bacteria. The MIC values of MRL-494 against E. coli (WT), E. coli (δtolC), E. coli (δtolC envA101), K. pneumonia, A. baumannii (WT), A. baumannii (δlpxC) , P. aeruginosa (efflux deficient), P. aeruginosa (WT), Staphylococcus aureus (methicillin-resistant) and Bacillus subtilis rpoB18 are 25 μM, 25 μM, 25 μM, 100 μM, 200 μM, 200 μM, 100 μM, 100 μM, 12.5 μM and 25 μM, respectively[2].
[1]. Hart EM, A small-molecule inhibitor of BamA impervious to efflux and the outer membrane permeability barrier. Proc Natl Acad Sci U S A. 2019 Oct 22;116(43):21748-21757. [2]. Hart EM, A small-molecule inhibitor of BamA impervious to efflux and the outer membrane permeability barrier. Proc Natl Acad Sci U S A. 2019 Oct 22;116(43):21748-21757.
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