Cargando…
CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens
The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobial-resistant pathogens requires a multifaceted effort that includes the discovery of novel therapeutic approaches. Here, we establish the capacity of t...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686536/ https://www.ncbi.nlm.nih.gov/pubmed/29138303 http://dx.doi.org/10.1128/mBio.01549-17 |
_version_ | 1783278797420756992 |
---|---|
author | Crawford, Matthew A. Fisher, Debra J. Leung, Lisa M. Lomonaco, Sara Lascols, Christine Cannatelli, Antonio Giani, Tommaso Rossolini, Gian Maria Doi, Yohei Goodlett, David R. Allard, Marc W. Sharma, Shashi K. Khan, Erum Ernst, Robert K. Hughes, Molly A. |
author_facet | Crawford, Matthew A. Fisher, Debra J. Leung, Lisa M. Lomonaco, Sara Lascols, Christine Cannatelli, Antonio Giani, Tommaso Rossolini, Gian Maria Doi, Yohei Goodlett, David R. Allard, Marc W. Sharma, Shashi K. Khan, Erum Ernst, Robert K. Hughes, Molly A. |
author_sort | Crawford, Matthew A. |
collection | PubMed |
description | The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobial-resistant pathogens requires a multifaceted effort that includes the discovery of novel therapeutic approaches. Here, we establish the capacity of the human CXC chemokines CXCL9 and CXCL10 to kill multidrug-resistant Gram-negative bacteria, including New Delhi metallo-beta-lactamase-1-producing Klebsiella pneumoniae and colistin-resistant members of the family Enterobacteriaceae that harbor the mobile colistin resistance protein MCR-1 and thus possess phosphoethanolamine-modified lipid A. Colistin-resistant K. pneumoniae isolates affected by genetic mutation of the PmrA/PmrB two-component system, a chromosomally encoded regulator of lipopolysaccharide modification, and containing 4-amino-4-deoxy-l-arabinose-modified lipid A were also found to be susceptible to chemokine-mediated antimicrobial activity. However, loss of PhoP/PhoQ autoregulatory control, caused by disruption of the gene encoding the negative regulator MgrB, limited the bactericidal effects of CXCL9 and CXCL10 in a variable, strain-specific manner. Cumulatively, these findings provide mechanistic insight into chemokine-mediated antimicrobial activity, highlight disparities amongst determinants of colistin resistance, and suggest that chemokine-mediated bactericidal effects merit additional investigation as a therapeutic avenue for treating infections caused by multidrug-resistant pathogens. |
format | Online Article Text |
id | pubmed-5686536 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-56865362017-11-17 CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens Crawford, Matthew A. Fisher, Debra J. Leung, Lisa M. Lomonaco, Sara Lascols, Christine Cannatelli, Antonio Giani, Tommaso Rossolini, Gian Maria Doi, Yohei Goodlett, David R. Allard, Marc W. Sharma, Shashi K. Khan, Erum Ernst, Robert K. Hughes, Molly A. mBio Research Article The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobial-resistant pathogens requires a multifaceted effort that includes the discovery of novel therapeutic approaches. Here, we establish the capacity of the human CXC chemokines CXCL9 and CXCL10 to kill multidrug-resistant Gram-negative bacteria, including New Delhi metallo-beta-lactamase-1-producing Klebsiella pneumoniae and colistin-resistant members of the family Enterobacteriaceae that harbor the mobile colistin resistance protein MCR-1 and thus possess phosphoethanolamine-modified lipid A. Colistin-resistant K. pneumoniae isolates affected by genetic mutation of the PmrA/PmrB two-component system, a chromosomally encoded regulator of lipopolysaccharide modification, and containing 4-amino-4-deoxy-l-arabinose-modified lipid A were also found to be susceptible to chemokine-mediated antimicrobial activity. However, loss of PhoP/PhoQ autoregulatory control, caused by disruption of the gene encoding the negative regulator MgrB, limited the bactericidal effects of CXCL9 and CXCL10 in a variable, strain-specific manner. Cumulatively, these findings provide mechanistic insight into chemokine-mediated antimicrobial activity, highlight disparities amongst determinants of colistin resistance, and suggest that chemokine-mediated bactericidal effects merit additional investigation as a therapeutic avenue for treating infections caused by multidrug-resistant pathogens. American Society for Microbiology 2017-11-14 /pmc/articles/PMC5686536/ /pubmed/29138303 http://dx.doi.org/10.1128/mBio.01549-17 Text en Copyright © 2017 Crawford et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Crawford, Matthew A. Fisher, Debra J. Leung, Lisa M. Lomonaco, Sara Lascols, Christine Cannatelli, Antonio Giani, Tommaso Rossolini, Gian Maria Doi, Yohei Goodlett, David R. Allard, Marc W. Sharma, Shashi K. Khan, Erum Ernst, Robert K. Hughes, Molly A. CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens |
title | CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens |
title_full | CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens |
title_fullStr | CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens |
title_full_unstemmed | CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens |
title_short | CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens |
title_sort | cxc chemokines exhibit bactericidal activity against multidrug-resistant gram-negative pathogens |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686536/ https://www.ncbi.nlm.nih.gov/pubmed/29138303 http://dx.doi.org/10.1128/mBio.01549-17 |
work_keys_str_mv | AT crawfordmatthewa cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens AT fisherdebraj cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens AT leunglisam cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens AT lomonacosara cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens AT lascolschristine cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens AT cannatelliantonio cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens AT gianitommaso cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens AT rossolinigianmaria cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens AT doiyohei cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens AT goodlettdavidr cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens AT allardmarcw cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens AT sharmashashik cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens AT khanerum cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens AT ernstrobertk cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens AT hughesmollya cxcchemokinesexhibitbactericidalactivityagainstmultidrugresistantgramnegativepathogens |