Reinforcing Lipid A Acylation on the Cell Surface of <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Promotes Cationic Antimicrobial Peptide Resistance and Desiccation Survival

ABSTRACT Acinetobacter baumannii is an emerging Gram-negative pathogen found in hospitals and intensive care units. In order to persist in hospital environments, A. baumannii withstands desiccative conditions and can rapidly develop multidrug resistance to conventional antibiotics. Cationic antimicr...

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Autores principales:	Joseph M. Boll, Ashley T. Tucker, Dustin R. Klein, Alexander M. Beltran, Jennifer S. Brodbelt, Bryan W. Davies, M. Stephen Trent
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/fbfcd8ed06b3473cb97bfcc0cbf702bc
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spelling	oai:doaj.org-article:fbfcd8ed06b3473cb97bfcc0cbf702bc2021-11-15T15:49:02ZReinforcing Lipid A Acylation on the Cell Surface of <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Promotes Cationic Antimicrobial Peptide Resistance and Desiccation Survival10.1128/mBio.00478-152150-7511https://doaj.org/article/fbfcd8ed06b3473cb97bfcc0cbf702bc2015-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00478-15https://doaj.org/toc/2150-7511ABSTRACT Acinetobacter baumannii is an emerging Gram-negative pathogen found in hospitals and intensive care units. In order to persist in hospital environments, A. baumannii withstands desiccative conditions and can rapidly develop multidrug resistance to conventional antibiotics. Cationic antimicrobial peptides (CAMPs) have served as therapeutic alternatives because they target the conserved lipid A component of the Gram-negative outer membrane to lyse the bacterial cell. However, many Gram-negative pathogenic bacteria, including A. baumannii, fortify their outer membrane with hepta-acylated lipid A to protect the cell from CAMP-dependent cell lysis. Whereas in Escherichia coli and Salmonella, increased production of the outer membrane acyltransferase PagP results in formation of protective hepta-acylated lipid A, which reinforces the lipopolysaccharide portion of the outer membrane barrier, A. baumannii does not carry a gene that encodes a PagP homolog. Instead, A. baumannii has evolved a PagP-independent mechanism to synthesize protective hepta-acylated lipid A. Taking advantage of a recently adapted A. baumannii genetic recombineering system, we characterized two putative acyltransferases in A. baumannii designated LpxLAb (A. baumannii LpxL) and LpxMAb (A. baumannii LpxM), which transfer one and two lauroyl (C12:0) acyl chains, respectively, during lipid A biosynthesis. Hepta-acylation of A. baumannii lipid A promoted resistance to vertebrate and polymyxin CAMPs, which are prescribed as last-resort treatment options. Intriguingly, our analysis also showed that LpxMAb-dependent acylation of lipid A is essential for A. baumannii desiccation survival, a key resistance mechanism for survival in hospital environments. Compounds that inhibit LpxMAb-dependent hepta-acylation of lipid A could act synergistically with CAMPs to provide innovative transmission prevention strategies and treat multidrug-resistant infections. IMPORTANCE Acinetobacter baumannii infections can be life threatening, and disease can progress in a variety of host tissues. Current antibiotic regimen and disinfectant strategies have failed to limit nosocomial A. baumannii infections. Instead, the rate of A. baumannii infection among health care communities has skyrocketed due to the bacterium's adaptability. Its aptitude for survival over extended periods on inanimate objects, such as catheters, respirators, and surfaces in intensive care units, or on the hands of health care workers and its ability to rapidly develop antibiotic resistance make A. baumannii a threat to health care communities. Emergence of multidrug- and extremely drug-resistant A. baumannii illustrates the ineffectiveness of current prevention and treatment options. Our analysis to understand how A. baumannii resists cationic antimicrobial peptide (CAMP)-mediated and desiccative killing revealed two lipid A acyltransferases that produce protective hepta-acylated lipid A. Our work suggests that inhibiting lipid A biosynthesis by targeting the acyltransferase LpxMAb (A. baumannii LpxM) could provide a novel target to combat this pathogen.Joseph M. BollAshley T. TuckerDustin R. KleinAlexander M. BeltranJennifer S. BrodbeltBryan W. DaviesM. Stephen TrentAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 3 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Joseph M. Boll Ashley T. Tucker Dustin R. Klein Alexander M. Beltran Jennifer S. Brodbelt Bryan W. Davies M. Stephen Trent Reinforcing Lipid A Acylation on the Cell Surface of <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Promotes Cationic Antimicrobial Peptide Resistance and Desiccation Survival
description	ABSTRACT Acinetobacter baumannii is an emerging Gram-negative pathogen found in hospitals and intensive care units. In order to persist in hospital environments, A. baumannii withstands desiccative conditions and can rapidly develop multidrug resistance to conventional antibiotics. Cationic antimicrobial peptides (CAMPs) have served as therapeutic alternatives because they target the conserved lipid A component of the Gram-negative outer membrane to lyse the bacterial cell. However, many Gram-negative pathogenic bacteria, including A. baumannii, fortify their outer membrane with hepta-acylated lipid A to protect the cell from CAMP-dependent cell lysis. Whereas in Escherichia coli and Salmonella, increased production of the outer membrane acyltransferase PagP results in formation of protective hepta-acylated lipid A, which reinforces the lipopolysaccharide portion of the outer membrane barrier, A. baumannii does not carry a gene that encodes a PagP homolog. Instead, A. baumannii has evolved a PagP-independent mechanism to synthesize protective hepta-acylated lipid A. Taking advantage of a recently adapted A. baumannii genetic recombineering system, we characterized two putative acyltransferases in A. baumannii designated LpxLAb (A. baumannii LpxL) and LpxMAb (A. baumannii LpxM), which transfer one and two lauroyl (C12:0) acyl chains, respectively, during lipid A biosynthesis. Hepta-acylation of A. baumannii lipid A promoted resistance to vertebrate and polymyxin CAMPs, which are prescribed as last-resort treatment options. Intriguingly, our analysis also showed that LpxMAb-dependent acylation of lipid A is essential for A. baumannii desiccation survival, a key resistance mechanism for survival in hospital environments. Compounds that inhibit LpxMAb-dependent hepta-acylation of lipid A could act synergistically with CAMPs to provide innovative transmission prevention strategies and treat multidrug-resistant infections. IMPORTANCE Acinetobacter baumannii infections can be life threatening, and disease can progress in a variety of host tissues. Current antibiotic regimen and disinfectant strategies have failed to limit nosocomial A. baumannii infections. Instead, the rate of A. baumannii infection among health care communities has skyrocketed due to the bacterium's adaptability. Its aptitude for survival over extended periods on inanimate objects, such as catheters, respirators, and surfaces in intensive care units, or on the hands of health care workers and its ability to rapidly develop antibiotic resistance make A. baumannii a threat to health care communities. Emergence of multidrug- and extremely drug-resistant A. baumannii illustrates the ineffectiveness of current prevention and treatment options. Our analysis to understand how A. baumannii resists cationic antimicrobial peptide (CAMP)-mediated and desiccative killing revealed two lipid A acyltransferases that produce protective hepta-acylated lipid A. Our work suggests that inhibiting lipid A biosynthesis by targeting the acyltransferase LpxMAb (A. baumannii LpxM) could provide a novel target to combat this pathogen.
format	article
author	Joseph M. Boll Ashley T. Tucker Dustin R. Klein Alexander M. Beltran Jennifer S. Brodbelt Bryan W. Davies M. Stephen Trent
author_facet	Joseph M. Boll Ashley T. Tucker Dustin R. Klein Alexander M. Beltran Jennifer S. Brodbelt Bryan W. Davies M. Stephen Trent
author_sort	Joseph M. Boll
title	Reinforcing Lipid A Acylation on the Cell Surface of <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Promotes Cationic Antimicrobial Peptide Resistance and Desiccation Survival
title_short	Reinforcing Lipid A Acylation on the Cell Surface of <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Promotes Cationic Antimicrobial Peptide Resistance and Desiccation Survival
title_full	Reinforcing Lipid A Acylation on the Cell Surface of <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Promotes Cationic Antimicrobial Peptide Resistance and Desiccation Survival
title_fullStr	Reinforcing Lipid A Acylation on the Cell Surface of <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Promotes Cationic Antimicrobial Peptide Resistance and Desiccation Survival
title_full_unstemmed	Reinforcing Lipid A Acylation on the Cell Surface of <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Promotes Cationic Antimicrobial Peptide Resistance and Desiccation Survival
title_sort	reinforcing lipid a acylation on the cell surface of <named-content content-type="genus-species">acinetobacter baumannii</named-content> promotes cationic antimicrobial peptide resistance and desiccation survival
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/fbfcd8ed06b3473cb97bfcc0cbf702bc
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Reinforcing Lipid A Acylation on the Cell Surface of <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Promotes Cationic Antimicrobial Peptide Resistance and Desiccation Survival

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