CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens

ABSTRACT 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 capa...

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Autores principales:	Matthew A. Crawford, Debra J. Fisher, Lisa M. Leung, Sara Lomonaco, Christine Lascols, Antonio Cannatelli, Tommaso Giani, Gian Maria Rossolini, Yohei Doi, David R. Goodlett, Marc W. Allard, Shashi K. Sharma, Erum Khan, Robert K. Ernst, Molly A. Hughes
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Gram negative antimicrobial resistance carbapenem chemokine colistin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7e3380c4f5744030a08e54e76e796919
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spelling	oai:doaj.org-article:7e3380c4f5744030a08e54e76e7969192021-11-15T15:51:55ZCXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens10.1128/mBio.01549-172150-7511https://doaj.org/article/7e3380c4f5744030a08e54e76e7969192017-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01549-17https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE As bacterial pathogens become resistant to multiple antibiotics, the infections they cause become increasingly difficult to treat. Carbapenem antibiotics provide an essential clinical barrier against multidrug-resistant bacteria; however, the dissemination of bacterial enzymes capable of inactivating carbapenems threatens the utility of these important antibiotics. Compounding this concern is the global spread of bacteria invulnerable to colistin, a polymyxin antibiotic considered to be a last line of defense against carbapenem-resistant pathogens. As the effectiveness of existing antibiotics erodes, it is critical to develop innovative antimicrobial therapies. To this end, we demonstrate that the chemokines CXCL9 and CXCL10 kill the most concerning carbapenem- and colistin-resistant pathogens. Our findings provide a unique and timely foundation for therapeutic strategies capable of countering antibiotic-resistant “superbugs.”Matthew A. CrawfordDebra J. FisherLisa M. LeungSara LomonacoChristine LascolsAntonio CannatelliTommaso GianiGian Maria RossoliniYohei DoiDavid R. GoodlettMarc W. AllardShashi K. SharmaErum KhanRobert K. ErnstMolly A. HughesAmerican Society for MicrobiologyarticleGram negativeantimicrobial resistancecarbapenemchemokinecolistinMicrobiologyQR1-502ENmBio, Vol 8, Iss 6 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Gram negative antimicrobial resistance carbapenem chemokine colistin Microbiology QR1-502
spellingShingle	Gram negative antimicrobial resistance carbapenem chemokine colistin Microbiology QR1-502 Matthew A. Crawford Debra J. Fisher Lisa M. Leung Sara Lomonaco Christine Lascols Antonio Cannatelli Tommaso Giani Gian Maria Rossolini Yohei Doi David R. Goodlett Marc W. Allard Shashi K. Sharma Erum Khan Robert K. Ernst Molly A. Hughes CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens
description	ABSTRACT 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. IMPORTANCE As bacterial pathogens become resistant to multiple antibiotics, the infections they cause become increasingly difficult to treat. Carbapenem antibiotics provide an essential clinical barrier against multidrug-resistant bacteria; however, the dissemination of bacterial enzymes capable of inactivating carbapenems threatens the utility of these important antibiotics. Compounding this concern is the global spread of bacteria invulnerable to colistin, a polymyxin antibiotic considered to be a last line of defense against carbapenem-resistant pathogens. As the effectiveness of existing antibiotics erodes, it is critical to develop innovative antimicrobial therapies. To this end, we demonstrate that the chemokines CXCL9 and CXCL10 kill the most concerning carbapenem- and colistin-resistant pathogens. Our findings provide a unique and timely foundation for therapeutic strategies capable of countering antibiotic-resistant “superbugs.”
format	article
author	Matthew A. Crawford Debra J. Fisher Lisa M. Leung Sara Lomonaco Christine Lascols Antonio Cannatelli Tommaso Giani Gian Maria Rossolini Yohei Doi David R. Goodlett Marc W. Allard Shashi K. Sharma Erum Khan Robert K. Ernst Molly A. Hughes
author_facet	Matthew A. Crawford Debra J. Fisher Lisa M. Leung Sara Lomonaco Christine Lascols Antonio Cannatelli Tommaso Giani Gian Maria Rossolini Yohei Doi David R. Goodlett Marc W. Allard Shashi K. Sharma Erum Khan Robert K. Ernst Molly A. Hughes
author_sort	Matthew A. Crawford
title	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_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_sort	cxc chemokines exhibit bactericidal activity against multidrug-resistant gram-negative pathogens
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/7e3380c4f5744030a08e54e76e796919
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CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens

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