Document Type
Article
Department
Pathology and Laboratory Medicine
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.
Publication (Name of Journal)
mBio
Recommended Citation
Khan, E.,
Crawford, M. A.,
Fisher, D. J.,
Leung, L. M.,
Lomonaco, S.,
Lascols, C.,
Cannatelli,, A.,
Rossolini, G. M.,
Doi, Y.,
Goodlett, D. R.
(2017). CXC chemokines exhibit bactericidal activity against multidrug-resistant gram-negative pathogens. mBio, 8(6), 1-12.
Available at:
https://ecommons.aku.edu/pakistan_fhs_mc_pathol_microbiol/736