University of Wisconsin-Madison School of Pharmacy, Pharmacy Practice Division, Madison, Wisconsin, USA.
Antimicrob Agents Chemother. 2013 Oct;57(10):5005-12. doi: 10.1128/AAC.00594-13. Epub 2013 Jul 29.
The activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA) is enhanced in the presence of subinhibitory concentrations of antistaphylococcal β-lactam antibiotics by an undefined mechanism. Given the variability in the penicillin-binding protein (PBP)-binding profiles of different β-lactam antibiotics, the purpose of this study was to examine the relative enhancement of DAP activity against MRSA by different β-lactam antibiotics to determine if a specific PBP-binding profile is associated with the ability to enhance the anti-MRSA activity of DAP. We determined that both broad- and narrow-spectrum β-lactam antibiotics known to exhibit PBP1 binding demonstrated potent enhancement of DAP anti-MRSA activity, whereas β-lactam antibiotics with minimal PBP1 binding (cefoxitin, ceftriaxone, cefaclor, and cefotaxime) were less effective. We suspect that PBP1 disruption by β-lactam antibiotics affects pathways of cell division in S. aureus that may be a compensatory response to DAP membrane insertion, resulting in DAP hypersusceptibility.
在亚抑菌浓度的抗葡萄球菌β-内酰胺类抗生素存在的情况下，达托霉素（DAP）对耐甲氧西林金黄色葡萄球菌（MRSA）的活性增强，其机制尚不清楚。鉴于不同β-内酰胺类抗生素的青霉素结合蛋白（PBP）结合谱存在差异，本研究旨在检测不同β-内酰胺类抗生素对 DAP 抗 MRSA 活性的相对增强作用，以确定是否存在与增强 DAP 抗 MRSA 活性相关的特定 PBP 结合谱。我们发现，与已知结合 PBP1 的广谱和窄谱β-内酰胺类抗生素一样，能显著增强 DAP 对 MRSA 的活性，而与 PBP1 结合最小的β-内酰胺类抗生素（头孢西丁、头孢曲松、头孢克洛和头孢噻肟）的效果则较差。我们推测，β-内酰胺类抗生素对 PBP1 的破坏影响了金黄色葡萄球菌细胞分裂的途径，这可能是对 DAP 膜插入的一种补偿性反应，导致 DAP 高度敏感。
