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Binding Studies Reveal Phospholipid Specificity and Its Role in the Calcium-Dependent Mechanism of Action of Daptomycin
ACS Infectious Diseases ( IF 5.3 ) Pub Date : 2021-08-18 , DOI: 10.1021/acsinfecdis.1c00316
Ioli Kotsogianni 1 , Thomas M Wood 1 , Francesca M Alexander 2 , Stephen A Cochrane 2 , Nathaniel I Martin 1
Affiliation  

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.

中文翻译:

结合研究揭示了磷脂特异性及其在达托霉素钙依赖性作用机制中的作用

随着抗生素越来越失去其临床疗效,多重耐药菌对全球健康构成严重威胁。对抗菌剂作用机制的分子水平理解在开发新的药物以对抗抗菌素耐药性威胁方面发挥着关键作用。达托霉素是唯一一种临床上使用的钙依赖性脂肽类抗生素,它选择性地破坏革兰氏阳性菌的细胞膜以发挥其杀菌作用。在这项研究中,我们使用等温滴定量热法来进一步表征驱动达托霉素结合的目标细菌磷脂的结构特征。我们的研究表明,达托霉素明显偏爱磷酸甘油头部基团。此外,与其他钙依赖性脂肽类抗生素不同,达托霉素对钙的结合强烈依赖于磷脂酰甘油的存在。这些研究为达托霉素的磷脂特异性和钙结合行为提供了新的见解。
更新日期:2021-09-10
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