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Chemokines kill bacteria without triggering antimicrobial resistance by binding anionic phospholipids

Pontejo, Sergio1; Martinez, Sophia1; Zhao, Allison1; Barnes, Kevin1; de Anda, Jaime2; Alimohamadi, Haleh2; Lee, Ernest2; Dishman, Acacia3; Volkman, Brian3; Wong, Gerard2; Garboczi, David1; Ballesteros, Angela4; Murphy, Philip1

Published May 22, 2025 on Dryad. https://doi.org/10.5061/dryad.dbrv15fc5

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Abstract

Classically, chemokines coordinate leukocyte trafficking; however, many chemokines also possess direct antibacterial activity. Yet, the bacterial killing mechanism of chemokines and the biochemical properties that define which members of the chemokine superfamily are antimicrobial remain poorly understood. We report that the antimicrobial activity of chemokines is defined by their ability to bind phosphatidylglycerol and cardiolipin, two anionic phospholipids commonly found in the bacterial plasma membrane. We show that only chemokines able to bind these two phospholipids kill bacteria and that they exert rapid bacteriostatic and bactericidal effects with a higher potency than the antimicrobial peptide beta-defensin 3. Both biochemical and genetic interference with the chemokine-cardiolipin interaction impaired microbial growth arrest, bacterial killing, and membrane disruption by chemokines. Moreover, unlike conventional antibiotics, E. coli failed to develop resistance when placed under increasing antimicrobial chemokine pressure in vitro. Thus, we have identified cardiolipin and phosphatidylglycerol as novel binding partners for chemokines responsible for chemokine antimicrobial action.