Chemokines Kill Bacteria without Triggering Antimicrobial Resistance by Binding Anionic Phospholipids 9268

Abstract Description Classically, chemokines coordinate leukocyte trafficking and many of them also exhibit direct antimicrobial properties. However, their antimicrobial mechanism is poorly understood. We have found that the antimicrobial activity of chemokines depends on their ability to bind anionic phospholipids on the bacterial plasma membrane, including cardiolipin and phosphatidylglycerol. Importantly, we proved that, unlike with traditional antibiotics, E. coli failed to develop resistance against antimicrobial chemokines. CCL21 is one of only two (CCL21 and CXCL9) antimicrobial chemokines that present an extended C-terminal tail containing many basic amino acids. Using recombinant full-length and C-tail truncated forms of CCL21, we found that while both forms signaled through CCR7, the cognate cellular receptor for CCL21, only full-length CCL21 killed E. coli(IC50 = 1.6 µM). Consistent with our proposed mechanism, we found that full-length CCL21 binds cardiolipin-containing liposomes, while the truncated form does not. Moreover, using a collection of peptides for the C-tail of CCL21, we were able to pinpoint the residues required for microbial killing and phospholipid-binding by CCL21. Our work uncovers the mechanism of action of antimicrobial chemokines and might guide the development of future chemokine-derived antimicrobial therapies. Funding Sources Division of Intramural Research, National Institute of Allergy and Infectious Diseases Topic Categories Cytokines and Chemokines and Their Receptors (CCR)