CXC chemokines exhibit bactericidal activity against multidrug-resistant gram-negative pathogens
PublisherAmerican Society for Microbiology
MetadataShow full item record
AbstractThe 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." Copyright 2017 Crawford et al.
SponsorsThese investigations were supported by U.S. National Institutes of Health grants R01 AI099097 (M.A.H.) and F32 AI108249 (M.A.C.), as well as the Henry Rose Carter Research Award (M.A.H.). S.L. received support by appointment to the Research Participation
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85039911192&doi=10.1128%2fmBio.01549-17&partnerID=40&md5=4ba257c8716541fa9c0d3ad3ce203496; http://hdl.handle.net/10713/10006
- [Results of a multicenter study investigating plasmid mediated colistin resistance genes (mcr-1 and mcr-2) in clinical Enterobacteriaceae ısolates from Turkey].
- Authors: Sarı AN, Süzük S, Karatuna O, Öğünç D, Karakoç AE, Çizmeci Z, Alışkan HE, Cömert F, Bakıcı MZ, Akpolat N, Çilli FF, Zer Y, Karataş A, Akgün Karapınar B, Bayramoğlu G, Özdamar M, Kalem F, Delialioğlu N, Aktaş E, Yılmaz N, Gürcan Ş, Gülay Z
- Issue date: 2017 Jul
- Polymyxin Combinations Combat <i>Escherichia coli</i> Harboring <i>mcr-1</i> and <i>bla</i><sub>NDM-5</sub>: Preparation for a Postantibiotic Era.
- Authors: Bulman ZP, Chen L, Walsh TJ, Satlin MJ, Qian Y, Bulitta JB, Peloquin CA, Holden PN, Nation RL, Li J, Kreiswirth BN, Tsuji BT
- Issue date: 2017 Jul 25
- Identification of the bacterial protein FtsX as a unique target of chemokine-mediated antimicrobial activity against Bacillus anthracis.
- Authors: Crawford MA, Lowe DE, Fisher DJ, Stibitz S, Plaut RD, Beaber JW, Zemansky J, Mehrad B, Glomski IJ, Strieter RM, Hughes MA
- Issue date: 2011 Oct 11
- An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance.
- Authors: Xu Y, Wei W, Lei S, Lin J, Srinivas S, Feng Y
- Issue date: 2018 Apr 10
- Contribution of Novel Amino Acid Alterations in PmrA or PmrB to Colistin Resistance in <i>mcr</i>-Negative Escherichia coli Clinical Isolates, Including Major Multidrug-Resistant Lineages O25b:H4-ST131-<i>H</i>30Rx and Non-x.
- Authors: Sato T, Shiraishi T, Hiyama Y, Honda H, Shinagawa M, Usui M, Kuronuma K, Masumori N, Takahashi S, Tamura Y, Yokota SI
- Issue date: 2018 Sep