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Title: 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 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.

Authors:
 [1];  [2];  [3];  [4];  [5];  [6];  [6];  [7];  [8];  [9];  [4];  [4];  [10];  [3];  [1];
+ Show Author Affiliations
  1. Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia (United States)
  2. Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA (United States)
  3. Department of Microbial Pathogenesis, School of Dentistry, University of Maryland-Baltimore, Baltimore, Maryland (United States)
  4. Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, Maryland (United States)
  5. National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia (United States)
  6. Department of Medical Biotechnologies, University of Siena, Siena (Italy)
  7. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Microbiology and Virology Unit, Florence Careggi University Hospital, Florence (Italy)
  8. Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (United States)
  9. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland—Baltimore, Baltimore, Maryland (United States)
  10. Department of Pathology and Microbiology, Aga Khan University, Karachi (Pakistan)
Publication Date:
Research Org.:
Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE; National Institute of Health; US Food and Drug Administration; U.S. Department of Homeland Security Science and Technology Directorate
OSTI Identifier:
1626135
Grant/Contract Number:  
SC0014664; R01 AI099097; F32 AI108249; HSHQPM-16-X- 00066
Resource Type:
Accepted Manuscript
Journal Name:
mBio (Online)
Additional Journal Information:
Journal Name: mBio (Online); Journal Volume: 8; Journal Issue: 6; Journal ID: ISSN 2150-7511
Publisher:
American Society for Microbiology (ASM)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Microbiology

Citation Formats

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., and Bush, Karen. CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens. United States: N. p., 2017. Web. doi:10.1128/mbio.01549-17.
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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., & Bush, Karen. CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens. United States. https://doi.org/10.1128/mbio.01549-17
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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., and Bush, Karen. Tue . "CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens". United States. https://doi.org/10.1128/mbio.01549-17. https://www.osti.gov/servlets/purl/1626135.
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@article{osti_1626135,
title = {CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens},
author = {Crawford, Matthew A. and Fisher, Debra J. and Leung, Lisa M. and Lomonaco, Sara and Lascols, Christine and Cannatelli, Antonio and Giani, Tommaso and Rossolini, Gian Maria and Doi, Yohei and Goodlett, David R. and Allard, Marc W. and Sharma, Shashi K. and Khan, Erum and Ernst, Robert K. and Hughes, Molly A. and Bush, Karen},
abstractNote = {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.},
doi = {10.1128/mbio.01549-17},
journal = {mBio (Online)},
number = 6,
volume = 8,
place = {United States},
year = {Tue Nov 14 00:00:00 EST 2017},
month = {Tue Nov 14 00:00:00 EST 2017}
}
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Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1128/mbio.01549-17
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Figures / Tables:

FIG 1 FIG 1: Bactericidal effects of CXC chemokines against CRE. (A) Carbapenem-resistant K. pneumoniae isolates and a species-matched control (ATCC 43816) are shown. Multilocus sequence types (MLSTs) and genes encoding the NDM-1 and/or OXA-48 carbapenemases are indicated. Antimicrobial susceptibilities (reported as MIC [ μg/ml]) were interpreted as resistant (red) or susceptiblemore » (green) in accordance with established breakpoints. The antibiotics tested were ampicillin (AMP), amoxicillin-clavulanic acid (AMC), AMP-sulbactam (SAM), piperacillin-tazobactam (TZP), cefazolin (CFZ), cefoxitin (FOX), cefotaxime (CTX), ceftriaxone (CRO), aztreonam (ATM), cefepime (FEP), ertapenem (ERT), doripenem (DOR), imipenem (IPM), meropenem (MEM), CST, amikacin (AMK), gentamicin (GEN), tobramycin (TOB), ciprofloxacin (CIP), levofloxacin (LVX), tetracycline (TET), tigecycline (TGC), and trimethoprim-sulfamethoxazole (SXT). Bacteria were treated with 48 μg/ml CXCL10 (B) or CXCL9 (C), and survival was measured by CFU determination (limit of detection, 500 CFU/ml; n.d., none detected). Data are expressed as percentages of the respective untreated-control value and represent the mean the standard error of the mean (n = 3). *, P < 0.05; **, P < 0.01 (compared to ATCC 43816). (D) CRE isolate BL12125 was treated with increasing concentrations of CXCL10. Data are expressed as percentages of the untreated-control value and represent the mean ± the standard error of the mean (n = 3). ***, P < 0.001 (compared to the untreated control).« less
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    Works referencing / citing this record:

    Resistome of carbapenem- and colistin-resistant Klebsiella pneumoniae clinical isolates
    journal, June 2018

    Mechanistic insights and therapeutic opportunities of antimicrobial chemokines
    journal, April 2019

    • Crawford, Matthew A.; Margulieux, Katie R.; Singh, Arpita
    • Seminars in Cell & Developmental Biology, Vol. 88
    • DOI: 10.1016/j.semcdb.2018.02.003
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