Identification of a novel MCR-1 variant displaying low level of co-resistance to β-lactam antibiotics that uncovers a potential novel antimicrobial peptide

doi:10.1101/2023.04.03.535341

KMS > 免疫化学研究所

	Identification of a novel MCR-1 variant displaying low level of co-resistance to β-lactam antibiotics that uncovers a potential novel antimicrobial peptide
	Liang, Lujie 1,2,3; Zhong, Lan-Lan 1,2,3; Wang, Lin 4; Zhou, Dianrong 1,2,3; Li, Yaxin 1,2,3; Li, Jiachen 1,2,3; Chen, Yong5 ; Liang, Wanfei 1,2,3; Wei, Wenjing 6; Zhang, Chenchen 6; Zhao, Hui 7; Lyu, Lingxuan 1,2,3; Stoesser, Nicole 8; Doi, Yohei 9,10; Paterson, David L 11; Bai, Fang 4,13; Feng, Siyuan 1,2,3,12; Tian, Guo-Bao 1,2,3,12
	2023-04-03
状态	已发表
摘要	The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. It is accepted that MCR-1 affects bacterial fitness, and this fitness cost correlates with bacterial membrane lipid A perturbation. However, the detailed molecular mechanism remains unclear. Here, we screened out a novel MCR-1 variant, named M6, with a two-point mutation that rendered a low level of co-resistance to {beta}-lactam antibiotics. Compared to wild-type (WT) MCR-1, this variant caused severe lipid A perturbation resulting in peptidoglycan layer remodelling and thus resulted in phenotypic co-resistance to {beta}-lactams. Moreover, we found that a lipid A loading cavity is localized at the linker domain of MCR-1 and governs colistin resistance and bacterial membrane permeability, and the mutated pocket of M6 facilitates the binding affinity of lipid A. More importantly, synthetic peptides derived from M6 achieved broad-spectrum antimicrobial activity. These findings provide insights into a potential vulnerability that could be exploited in future antimicrobial drug design.
DOI	10.1101/2023.04.03.535341
相关网址	查看原文
出处	bioRxiv
WOS记录号	PPRN:53489763
WOS类目	Microbiology
资助项目	National Natural Science Foundation of China[
文献类型	预印本
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/348335
专题	免疫化学研究所生命科学与技术学院_特聘教授组_陈勇组
作者单位	1.Sun Yat Sen Univ, Zhongshan Sch Med, Dept Immunol & Microbiol, Guangzhou 510080, Guangdong, Peoples R China 2.Fujita Hlth Univ, Dept Microbiol, Sch Med, Aichi, Japan 3.Univ Queensland, Ctr Clin Res UQCCR, Fac Med, Brisbane, Australia 4.Sun Yat sen Univ, Zhongshan Sch Med, Dept Immunol & Microbiol, 74 Zhongshan 2nd Rd, Guangzhou 510080, Peoples R China 5.Shanghai Tech Univ, Shanghai Inst Adv Immunochem Studies, Sch Life Sci & Technol, Shanghai, Peoples R China 6.Sun Yat sen Univ, Affiliated Hosp 1, Adv Med Technol Ctr, Zhongshan Sch Med, Guangzhou 510080, Peoples R China 7.Sun Yat sen Univ, Key Lab Trop Dis Control, Minist Educ, Guangzhou 510080, Peoples R China 8.Shanghai Tech Univ, Shanghai Inst Adv Immunochem Studies, Sch Life Sci & Technol, Shanghai, Peoples R China 9.Chengdu Med Coll, Sch Lab Med, Chengdu, Peoples R China 10.Ctr TB Control Guangdong Prov, Guangzhou 510630, Guangdong, Peoples R China 11.Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Lab Med, Guangzhou 510000, Guangdong, Peoples R China 12.Univ Oxford, Nuffield Dept Med, Modernising Med Microbiol, Oxford, England 13.Univ Pittsburgh, Sch Med, Pittsburgh, PA, USA
推荐引用方式 GB/T 7714	Liang, Lujie,Zhong, Lan-Lan,Wang, Lin,et al. Identification of a novel MCR-1 variant displaying low level of co-resistance to β-lactam antibiotics that uncovers a potential novel antimicrobial peptide. 2023.