Background and objectives: The continued rise and spread of antimicrobial resistance among bacterial pathogens poses a critical threat to global health. Of particular concern is resistance against carbapenems and colistin, antimicrobial agents regarded as last-line defenses for treating infections caused by Gram-negative pathogens. Countering the risks posed by antimicrobial resistant bacterial pathogens will require a multifaceted effort that includes the discovery of novel therapeutic approaches. Here we present the antibacterial capacity of human CXC chemokines to kill multidrug-resistant Gram-negative pathogens. Materials and methods: Multidrug-resistant Klebsiella pneumoniae, Escherichia coli, and Acinetobacter baumannii isolates were obtained from Pakistan, Italy, and the United States. Antimicrobial resistance was established by Vitek. Susceptibility to recombinant human CXCL9 and CXCL10 was measured by colony-forming unit determination. New Delhi metalloprotease-1 (NDM-1) and oxacillinase-48 (OXA-48) carbapenemases were identified by PCR. Lipid A chemical modifications conferring colistin resistance were detected using MALDI-TOF mass spectrometry. Results: Multidrug-resistant bacteria, including NDM-1- and OXA-48-producing isolates, were susceptible to chemokine-mediated antimicrobial activity. Colistin resistance arising from disruptions in chromosomal loci (e.g. mgrB and pmrB), and consequent modification of lipid A with L-4-aminoarabinose (L-Ara4N), resulted in varying levels of isolate-specific resistance against CXCL10; genetic complementation reversed these phenotypes. Of interest, colistin-resistant E. coli harboring the plasmid-borne mcr-1 gene were fully susceptible to CXCL10-mediated killing despite the presence of phosphoethanolamine (pEtN)-modified lipid A in the outer membrane of these organisms. Conclusion: Our observations demonstrate that CXC chemokines are capable of killing multidrug-resistant, carbapenemase-producing Gram-negative bacterial pathogens. In regards to colistin-resistant bacteria, L-Ara4N-modified lipid A limited killing by CXCL10; however, pEtN-modified lipid A did not. This distinction may reflect disparate effects of L-Ara4N and pEtN modification on outer membrane charge neutralization and / or permeability. Collectively, our findings will inform the development of innovative strategies for treating infections caused by antimicrobial-resistant pathogens.
CXC Chemokines Mediate Antimicrobial Activity against Multidrug-Resistant Gram-Negative Pathogens
LOMONACO, Sara;
2017-01-01
Abstract
Background and objectives: The continued rise and spread of antimicrobial resistance among bacterial pathogens poses a critical threat to global health. Of particular concern is resistance against carbapenems and colistin, antimicrobial agents regarded as last-line defenses for treating infections caused by Gram-negative pathogens. Countering the risks posed by antimicrobial resistant bacterial pathogens will require a multifaceted effort that includes the discovery of novel therapeutic approaches. Here we present the antibacterial capacity of human CXC chemokines to kill multidrug-resistant Gram-negative pathogens. Materials and methods: Multidrug-resistant Klebsiella pneumoniae, Escherichia coli, and Acinetobacter baumannii isolates were obtained from Pakistan, Italy, and the United States. Antimicrobial resistance was established by Vitek. Susceptibility to recombinant human CXCL9 and CXCL10 was measured by colony-forming unit determination. New Delhi metalloprotease-1 (NDM-1) and oxacillinase-48 (OXA-48) carbapenemases were identified by PCR. Lipid A chemical modifications conferring colistin resistance were detected using MALDI-TOF mass spectrometry. Results: Multidrug-resistant bacteria, including NDM-1- and OXA-48-producing isolates, were susceptible to chemokine-mediated antimicrobial activity. Colistin resistance arising from disruptions in chromosomal loci (e.g. mgrB and pmrB), and consequent modification of lipid A with L-4-aminoarabinose (L-Ara4N), resulted in varying levels of isolate-specific resistance against CXCL10; genetic complementation reversed these phenotypes. Of interest, colistin-resistant E. coli harboring the plasmid-borne mcr-1 gene were fully susceptible to CXCL10-mediated killing despite the presence of phosphoethanolamine (pEtN)-modified lipid A in the outer membrane of these organisms. Conclusion: Our observations demonstrate that CXC chemokines are capable of killing multidrug-resistant, carbapenemase-producing Gram-negative bacterial pathogens. In regards to colistin-resistant bacteria, L-Ara4N-modified lipid A limited killing by CXCL10; however, pEtN-modified lipid A did not. This distinction may reflect disparate effects of L-Ara4N and pEtN modification on outer membrane charge neutralization and / or permeability. Collectively, our findings will inform the development of innovative strategies for treating infections caused by antimicrobial-resistant pathogens.
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