Deciphering MCR-2 Colistin Resistance

ABSTRACT Antibiotic resistance is a prevalent problem in public health worldwide. In general, the carbapenem β-lactam antibiotics are considered a final resort against lethal infections by multidrug-resistant bacteria. Colistin is a cationic polypeptide antibiotic and acts as the last line of defens...

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Autores principales:	Jian Sun, Yongchang Xu, Rongsui Gao, Jingxia Lin, Wenhui Wei, Swaminath Srinivas, Defeng Li, Run-Shi Yang, Xing-Ping Li, Xiao-Ping Liao, Ya-Hong Liu, Youjun Feng
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	colistin resistance dissemination domain swapping MCR-1 MCR-2 origin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/15119732c1d74c338263ed2a18e1e543
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spelling	oai:doaj.org-article:15119732c1d74c338263ed2a18e1e5432021-11-15T15:51:29ZDeciphering MCR-2 Colistin Resistance10.1128/mBio.00625-172150-7511https://doaj.org/article/15119732c1d74c338263ed2a18e1e5432017-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00625-17https://doaj.org/toc/2150-7511ABSTRACT Antibiotic resistance is a prevalent problem in public health worldwide. In general, the carbapenem β-lactam antibiotics are considered a final resort against lethal infections by multidrug-resistant bacteria. Colistin is a cationic polypeptide antibiotic and acts as the last line of defense for treatment of carbapenem-resistant bacteria. Very recently, a new plasmid-borne colistin resistance gene, mcr-2, was revealed soon after the discovery of the paradigm gene mcr-1, which has disseminated globally. However, the molecular mechanisms for MCR-2 colistin resistance are poorly understood. Here we show a unique transposon unit that facilitates the acquisition and transfer of mcr-2. Evolutionary analyses suggested that both MCR-2 and MCR-1 might be traced to their cousin phosphoethanolamine (PEA) lipid A transferase from a known polymyxin producer, Paenibacillus. Transcriptional analyses showed that the level of mcr-2 transcripts is relatively higher than that of mcr-1. Genetic deletions revealed that the transmembrane regions (TM1 and TM2) of both MCR-1 and MCR-2 are critical for their location and function in bacterial periplasm, and domain swapping indicated that the TM2 is more efficient than TM1. Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) confirmed that all four MCR proteins (MCR-1, MCR-2, and two chimeric versions [TM1-MCR-2 and TM2-MCR-1]) can catalyze chemical modification of lipid A moiety anchored on lipopolysaccharide (LPS) with the addition of phosphoethanolamine to the phosphate group at the 4′ position of the sugar. Structure-guided site-directed mutagenesis defined an essential 6-residue-requiring zinc-binding/catalytic motif for MCR-2 colistin resistance. The results further our mechanistic understanding of transferable colistin resistance, providing clues to improve clinical therapeutics targeting severe infections by MCR-2-containing pathogens. IMPORTANCE Carbapenem and colistin are the last line of refuge in fighting multidrug-resistant Gram-negative pathogens. MCR-2 is a newly emerging variant of the mobilized colistin resistance protein MCR-1, posing a potential challenge to public health. Here we report transfer of the mcr-2 gene by a unique transposal event and its possible origin. Distribution of MCR-2 in bacterial periplasm is proposed to be a prerequisite for its role in the context of biochemistry and the colistin resistance. We also define the genetic requirement of a zinc-binding/catalytic motif for MCR-2 colistin resistance. This represents a glimpse of transferable colistin resistance by MCR-2.Jian SunYongchang XuRongsui GaoJingxia LinWenhui WeiSwaminath SrinivasDefeng LiRun-Shi YangXing-Ping LiXiao-Ping LiaoYa-Hong LiuYoujun FengAmerican Society for Microbiologyarticlecolistin resistancedisseminationdomain swappingMCR-1MCR-2originMicrobiologyQR1-502ENmBio, Vol 8, Iss 3 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	colistin resistance dissemination domain swapping MCR-1 MCR-2 origin Microbiology QR1-502
spellingShingle	colistin resistance dissemination domain swapping MCR-1 MCR-2 origin Microbiology QR1-502 Jian Sun Yongchang Xu Rongsui Gao Jingxia Lin Wenhui Wei Swaminath Srinivas Defeng Li Run-Shi Yang Xing-Ping Li Xiao-Ping Liao Ya-Hong Liu Youjun Feng Deciphering MCR-2 Colistin Resistance
description	ABSTRACT Antibiotic resistance is a prevalent problem in public health worldwide. In general, the carbapenem β-lactam antibiotics are considered a final resort against lethal infections by multidrug-resistant bacteria. Colistin is a cationic polypeptide antibiotic and acts as the last line of defense for treatment of carbapenem-resistant bacteria. Very recently, a new plasmid-borne colistin resistance gene, mcr-2, was revealed soon after the discovery of the paradigm gene mcr-1, which has disseminated globally. However, the molecular mechanisms for MCR-2 colistin resistance are poorly understood. Here we show a unique transposon unit that facilitates the acquisition and transfer of mcr-2. Evolutionary analyses suggested that both MCR-2 and MCR-1 might be traced to their cousin phosphoethanolamine (PEA) lipid A transferase from a known polymyxin producer, Paenibacillus. Transcriptional analyses showed that the level of mcr-2 transcripts is relatively higher than that of mcr-1. Genetic deletions revealed that the transmembrane regions (TM1 and TM2) of both MCR-1 and MCR-2 are critical for their location and function in bacterial periplasm, and domain swapping indicated that the TM2 is more efficient than TM1. Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) confirmed that all four MCR proteins (MCR-1, MCR-2, and two chimeric versions [TM1-MCR-2 and TM2-MCR-1]) can catalyze chemical modification of lipid A moiety anchored on lipopolysaccharide (LPS) with the addition of phosphoethanolamine to the phosphate group at the 4′ position of the sugar. Structure-guided site-directed mutagenesis defined an essential 6-residue-requiring zinc-binding/catalytic motif for MCR-2 colistin resistance. The results further our mechanistic understanding of transferable colistin resistance, providing clues to improve clinical therapeutics targeting severe infections by MCR-2-containing pathogens. IMPORTANCE Carbapenem and colistin are the last line of refuge in fighting multidrug-resistant Gram-negative pathogens. MCR-2 is a newly emerging variant of the mobilized colistin resistance protein MCR-1, posing a potential challenge to public health. Here we report transfer of the mcr-2 gene by a unique transposal event and its possible origin. Distribution of MCR-2 in bacterial periplasm is proposed to be a prerequisite for its role in the context of biochemistry and the colistin resistance. We also define the genetic requirement of a zinc-binding/catalytic motif for MCR-2 colistin resistance. This represents a glimpse of transferable colistin resistance by MCR-2.
format	article
author	Jian Sun Yongchang Xu Rongsui Gao Jingxia Lin Wenhui Wei Swaminath Srinivas Defeng Li Run-Shi Yang Xing-Ping Li Xiao-Ping Liao Ya-Hong Liu Youjun Feng
author_facet	Jian Sun Yongchang Xu Rongsui Gao Jingxia Lin Wenhui Wei Swaminath Srinivas Defeng Li Run-Shi Yang Xing-Ping Li Xiao-Ping Liao Ya-Hong Liu Youjun Feng
author_sort	Jian Sun
title	Deciphering MCR-2 Colistin Resistance
title_short	Deciphering MCR-2 Colistin Resistance
title_full	Deciphering MCR-2 Colistin Resistance
title_fullStr	Deciphering MCR-2 Colistin Resistance
title_full_unstemmed	Deciphering MCR-2 Colistin Resistance
title_sort	deciphering mcr-2 colistin resistance
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/15119732c1d74c338263ed2a18e1e543
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Deciphering MCR-2 Colistin Resistance

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