An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance

ABSTRACT Polymyxins, a family of cationic antimicrobial cyclic peptides, act as a last line of defense against severe infections by Gram-negative pathogens with carbapenem resistance. In addition to the intrinsic resistance to polymyxin E (colistin) conferred by Neisseria eptA, the plasmid-borne mob...

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Autores principales:	Yongchang Xu, Wenhui Wei, Sheng Lei, Jingxia Lin, Swaminath Srinivas, Youjun Feng
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	enteric bacteria EptA lipid A MCR-1 MCR-2 polymyxin resistance Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/977dbc397dc24d05840738adaebbe8c4
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spelling	oai:doaj.org-article:977dbc397dc24d05840738adaebbe8c42021-11-15T15:53:27ZAn Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance10.1128/mBio.02317-172150-7511https://doaj.org/article/977dbc397dc24d05840738adaebbe8c42018-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02317-17https://doaj.org/toc/2150-7511ABSTRACT Polymyxins, a family of cationic antimicrobial cyclic peptides, act as a last line of defense against severe infections by Gram-negative pathogens with carbapenem resistance. In addition to the intrinsic resistance to polymyxin E (colistin) conferred by Neisseria eptA, the plasmid-borne mobilized colistin resistance gene mcr-1 has been disseminated globally since the first discovery in Southern China, in late 2015. However, the molecular mechanisms for both intrinsic and transferable resistance to colistin remain largely unknown. Here, we aim to address this gap in the knowledge of these proteins. Structural and functional analyses of EptA and MCR-1 and -2 have defined a conserved 12-residue cavity that is required for the entry of the lipid substrate, phosphatidylethanolamine (PE). The in vitro and in vivo data together have allowed us to visualize the similarities in catalytic activity shared by EptA and MCR-1 and -2. The expression of either EptA or MCR-1 or -2 is shown to remodel the surface of enteric bacteria (e.g., Escherichia coli, Salmonella enterica, Klebsiella pneumoniae, etc.), rendering them resistant to colistin. The parallels in the PE substrate-binding cavities among EptA, MCR-1, and MCR-2 provide a comprehensive understanding of both intrinsic and transferable colistin resistance. Domain swapping between EptA and MCR-1 and -2 reveals that the two domains (transmembrane [TM] region and phosphoethanolamine [PEA] transferase) are not functionally exchangeable. Taken together, the results represent a common mechanism for intrinsic and transferable PEA resistance to polymyxin, a last-resort antibiotic against multidrug-resistant pathogens. IMPORTANCE EptA and MCR-1 and -2 remodel the outer membrane, rendering bacteria resistant to colistin, a final resort against carbapenem-resistant pathogens. Structural and functional analyses of EptA and MCR-1 and -2 reveal parallel PE lipid substrate-recognizing cavities, which explains intrinsic and transferable colistin resistance in gut bacteria. A similar mechanism is proposed for the catalytic activities of EptA and MCR-1 and -2. Together, they constitute a common mechanism for intrinsic and transferable polymyxin resistance.Yongchang XuWenhui WeiSheng LeiJingxia LinSwaminath SrinivasYoujun FengAmerican Society for Microbiologyarticleenteric bacteriaEptAlipid AMCR-1MCR-2polymyxin resistanceMicrobiologyQR1-502ENmBio, Vol 9, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	enteric bacteria EptA lipid A MCR-1 MCR-2 polymyxin resistance Microbiology QR1-502
spellingShingle	enteric bacteria EptA lipid A MCR-1 MCR-2 polymyxin resistance Microbiology QR1-502 Yongchang Xu Wenhui Wei Sheng Lei Jingxia Lin Swaminath Srinivas Youjun Feng An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance
description	ABSTRACT Polymyxins, a family of cationic antimicrobial cyclic peptides, act as a last line of defense against severe infections by Gram-negative pathogens with carbapenem resistance. In addition to the intrinsic resistance to polymyxin E (colistin) conferred by Neisseria eptA, the plasmid-borne mobilized colistin resistance gene mcr-1 has been disseminated globally since the first discovery in Southern China, in late 2015. However, the molecular mechanisms for both intrinsic and transferable resistance to colistin remain largely unknown. Here, we aim to address this gap in the knowledge of these proteins. Structural and functional analyses of EptA and MCR-1 and -2 have defined a conserved 12-residue cavity that is required for the entry of the lipid substrate, phosphatidylethanolamine (PE). The in vitro and in vivo data together have allowed us to visualize the similarities in catalytic activity shared by EptA and MCR-1 and -2. The expression of either EptA or MCR-1 or -2 is shown to remodel the surface of enteric bacteria (e.g., Escherichia coli, Salmonella enterica, Klebsiella pneumoniae, etc.), rendering them resistant to colistin. The parallels in the PE substrate-binding cavities among EptA, MCR-1, and MCR-2 provide a comprehensive understanding of both intrinsic and transferable colistin resistance. Domain swapping between EptA and MCR-1 and -2 reveals that the two domains (transmembrane [TM] region and phosphoethanolamine [PEA] transferase) are not functionally exchangeable. Taken together, the results represent a common mechanism for intrinsic and transferable PEA resistance to polymyxin, a last-resort antibiotic against multidrug-resistant pathogens. IMPORTANCE EptA and MCR-1 and -2 remodel the outer membrane, rendering bacteria resistant to colistin, a final resort against carbapenem-resistant pathogens. Structural and functional analyses of EptA and MCR-1 and -2 reveal parallel PE lipid substrate-recognizing cavities, which explains intrinsic and transferable colistin resistance in gut bacteria. A similar mechanism is proposed for the catalytic activities of EptA and MCR-1 and -2. Together, they constitute a common mechanism for intrinsic and transferable polymyxin resistance.
format	article
author	Yongchang Xu Wenhui Wei Sheng Lei Jingxia Lin Swaminath Srinivas Youjun Feng
author_facet	Yongchang Xu Wenhui Wei Sheng Lei Jingxia Lin Swaminath Srinivas Youjun Feng
author_sort	Yongchang Xu
title	An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance
title_short	An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance
title_full	An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance
title_fullStr	An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance
title_full_unstemmed	An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance
title_sort	evolutionarily conserved mechanism for intrinsic and transferable polymyxin resistance
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/977dbc397dc24d05840738adaebbe8c4
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An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance

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