Dou Qin, Yuan Jin, Yu Rilei, Yang Jiahui, Wang Jiayi, Zhu Yuxiang, Zhong Jing, Long Hongan, Liu Zhiqing, Wang Xianghong, Li Yuying, Xiao Yichen, Liang Jiazhen, Zhang Xiao-Hua, Wang Yan
College of Marine Life Sciences, and Institute of Evolution & Marine Biodiversity Ocean University of China Qingdao China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center Sun Yat-Sen University Guangzhou China.
mLife. 2022 Mar 24;1(4):428-442. doi: 10.1002/mlf2.12016. eCollection 2022 Dec.
Antibiotic resistance in gram-negative pathogens has become one of the most serious global public health threats. The role of the -acyl homoserine lactone (AHL)-mediated signaling pathway, which is widespread in gram-negative bacteria, in the bacterial resistance process should be studied in depth. Here, we report a degrading enzyme of AHLs, MomL, that inhibits the antibiotic resistance of through a novel mechanism. The MomL-mediated reactivation of kanamycin is highly associated with the -mediated starvation stringent response. The degradation of AHLs by MomL results in the inability of LasR to activate , which, in turn, stops the activation of downstream . Further results show that directly regulates the type VI secretion system H2-T6SS. Under MomL treatment, inactivated RpoS fails to regulate H2-T6SS; therefore, the expression of effector phospholipase A is reduced, and the adaptability of bacteria to antibiotics is weakened. MomL in combination with kanamycin is effective against a wide range of gram-negative pathogenic bacteria. Therefore, this study reports a MomL-antibiotic treatment strategy on antibiotic-resistant bacteria and reveals its mechanism of action.
革兰氏阴性病原体中的抗生素耐药性已成为最严重的全球公共卫生威胁之一。在革兰氏阴性细菌中广泛存在的N-酰基高丝氨酸内酯（AHL）介导的信号通路在细菌耐药过程中的作用应深入研究。在此，我们报道了一种AHLs降解酶MomL，它通过一种新机制抑制细菌的抗生素耐药性。MomL介导的卡那霉素再激活与ppGpp介导的饥饿应急反应高度相关。MomL对AHLs的降解导致LasR无法激活PqsR，进而阻止下游基因的激活。进一步结果表明，PqsR直接调控VI型分泌系统H2-T6SS。在MomL处理下，失活的RpoS无法调控H2-T6SS；因此，效应物磷脂酶A的表达降低，细菌对抗生素的适应性减弱。MomL与卡那霉素联合对多种革兰氏阴性病原菌有效。因此，本研究报道了一种针对耐药菌的MomL-抗生素治疗策略并揭示了其作用机制。
