CXC chemokines exhibit bactericidal activity against multidrug-resistant gram-negative pathogens

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

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobialresistant 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 aunique and timely foundation for therapeutic strategies capable of countering antibiotic-resistant “superbugs.”

Original languageEnglish
Article numbere01549-17
JournalmBio
Volume8
Issue number6
DOIs
Publication statusPublished - 01-11-2017

Fingerprint

Colistin
CXC Chemokines
Carbapenems
Anti-Bacterial Agents
Chemokine CXCL9
Chemokines
Chemokine CXCL10
Lipid A
Klebsiella pneumoniae
Polymyxins
Bacteria
Investigational Therapies
Enterobacteriaceae
Infection
Gram-Negative Bacteria
Lipopolysaccharides
Therapeutics
Mutation
Enzymes
Genes

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Virology

Cite this

Crawford, M. A., Fisher, D. J., Leung, L. M., Lomonaco, S., Lascols, C., Cannatelli, A., ... Hughes, M. A. (2017). CXC chemokines exhibit bactericidal activity against multidrug-resistant gram-negative pathogens. mBio, 8(6), [e01549-17]. https://doi.org/10.1128/mBio.01549-17
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. In: mBio. 2017 ; Vol. 8, No. 6.
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abstract = "The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobialresistant 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 aunique and timely foundation for therapeutic strategies capable of countering antibiotic-resistant “superbugs.”",
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Crawford, MA, Fisher, DJ, Leung, LM, Lomonaco, S, Lascols, C, Cannatelli, A, Giani, T, Rossolini, GM, Doi, Y, Goodlett, DR, Allard, MW, Sharma, SK, Khan, E, Ernst, RK & Hughes, MA 2017, 'CXC chemokines exhibit bactericidal activity against multidrug-resistant gram-negative pathogens', mBio, vol. 8, no. 6, e01549-17. https://doi.org/10.1128/mBio.01549-17

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.

In: mBio, Vol. 8, No. 6, e01549-17, 01.11.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - CXC chemokines exhibit bactericidal activity against multidrug-resistant gram-negative pathogens

AU - Crawford, Matthew A.

AU - Fisher, Debra J.

AU - Leung, Lisa M.

AU - Lomonaco, Sara

AU - Lascols, Christine

AU - Cannatelli, Antonio

AU - Giani, Tommaso

AU - Rossolini, Gian Maria

AU - Doi, Yohei

AU - Goodlett, David R.

AU - Allard, Marc W.

AU - Sharma, Shashi K.

AU - Khan, Erum

AU - Ernst, Robert K.

AU - Hughes, Molly A.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobialresistant 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 aunique and timely foundation for therapeutic strategies capable of countering antibiotic-resistant “superbugs.”

AB - The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobialresistant 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 aunique and timely foundation for therapeutic strategies capable of countering antibiotic-resistant “superbugs.”

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Crawford MA, Fisher DJ, Leung LM, Lomonaco S, Lascols C, Cannatelli A et al. CXC chemokines exhibit bactericidal activity against multidrug-resistant gram-negative pathogens. mBio. 2017 Nov 1;8(6). e01549-17. https://doi.org/10.1128/mBio.01549-17