Binding Studies Reveal Phospholipid Specificity and Its Role in the Calcium-Dependent Mechanism of Action of Daptomycin

• DOI: 10.1021/acsinfecdis.1c00316
• Publication Date: 2021-08-18T13:13:06Z
• Authors: Ioli Kotsogianni; Thomas M. Wood; Francesca M. Alex...; Stephen A. Cochrane; Nathaniel I. Martin
• Keywords: Daptomycin; Phosphatidylglycerol; Isothermal Titration Calorimetry; Lipopeptide; Mechanism of Action

Multidrug-resistant bacteria pose a serious global health threat as antibiotics are increasingly losing their clinical efficacy. A molecular level understanding of the mechanism action antimicrobials plays key role in developing new agents to combat antimicrobial resistance. Daptomycin, only clinically used calcium-dependent lipopeptide antibiotic, selectively disrupts Gram-positive bacterial membranes illicit its bactericidal effect. In this study, we use isothermal titration calorimetry further characterize structural features target phospholipids that drive daptomycin binding. Our studies reveal shows clear preference for phosphoglycerol headgroup. Furthermore, unlike other antibiotics, calcium binding by is strongly dependent on presence phosphatidylglycerol. These investigations provide insights into daptomycin's phospholipid specificity and behavior.