Open AccessBinding Studies Reveal Phospholipid Specificity and Its Role in the Calcium-Dependent Mechanism of Action of Daptomycin
Author(s) -
Ioli Kotsogianni,
Thomas M. Wood,
Francesca M. Alexander,
Stephen A. Cochrane,
Nathaniel I. Martin
Publication year - 2021
Publication title -
acs infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.324
H-Index - 39
ISSN - 2373-8227
DOI - 10.1021/acsinfecdis.1c00316
Subject(s) - daptomycin , isothermal titration calorimetry , phosphatidylglycerol , lipopeptide , calcium , antibiotics , phospholipid , mechanism of action , antimicrobial , microbiology and biotechnology , chemistry , bacteria , biochemistry , biology , membrane , vancomycin , staphylococcus aureus , organic chemistry , phosphatidylcholine , in vitro , genetics
Multidrug-resistant bacteria pose a serious global health threat as antibiotics are increasingly losing their clinical efficacy. A molecular level understanding of the mechanism of action of antimicrobials plays a key role in developing new agents to combat the threat of antimicrobial resistance. Daptomycin, the only clinically used calcium-dependent lipopeptide antibiotic, selectively disrupts Gram-positive bacterial membranes to illicit its bactericidal effect. In this study, we use isothermal titration calorimetry to further characterize the structural features of the target bacterial phospholipids that drive daptomycin binding. Our studies reveal that daptomycin shows a clear preference for the phosphoglycerol headgroup. Furthermore, unlike other calcium-dependent lipopeptide antibiotics, calcium binding by daptomycin is strongly dependent on the presence of phosphatidylglycerol. These investigations provide new insights into daptomycin's phospholipid specificity and calcium binding behavior.