Proteomic Correlates of Enhanced Daptomycin Activity following β-Lactam Preconditioning in Daptomycin-Resistant, Methicillin-Resistant Staphylococcus aureus.
Proteomic Correlates of Enhanced Daptomycin Activity following β-Lactam Preconditioning in Daptomycin-Resistant, Methicillin-Resistant Staphylococcus aureus.
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达托霉素抗性、甲氧西林抗性金黄色葡萄球菌β-内酰胺预处理后增强达托霉素活性的蛋白质组相关性。
DOI：
10.1128/aac.02017-21
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发表时间：
2022
影响因子：
4.9
通讯作者：
Rose,WarrenE
中科院分区：
文献类型：
--
作者：
Lew,Cassandra;PellitteriHahn,Molly;Scarlett,Cameron;Rottier,Aaron;Berti,AndrewD;Proctor,RichardA;Bayer,ArnoldS;Rose,WarrenE
达托霉素（DAP）耐药（DAP-R）、甲氧西林耐药金黄色葡萄球菌（MRSA）感染的临床治疗选择相对有限。目前的治疗策略通常利用DAP加β-内酰胺的潜在协同活性;然而，其组合功效的潜在机制可能是复杂的，并且仍然不完全理解。我们最近发现，体外β-内酰胺传代可以使DAP-R菌株重新敏感为DAP-敏感（DAP-S）表型。为了进一步研究所选β-内酰胺预处理对DAP + β-内酰胺联合治疗疗效的影响，我们使用了DAP-R菌株D 712。我们使用DAP-R菌株D 712研究了6种此类组合，其特征在于β-内酰胺具有广泛的青霉素结合蛋白靶向特征（PBP-1至PBP-4）。值得注意的是，与单独使用DAP或同时使用两种抗生素相比，先使用每种β-内酰胺抗生素预处理（顺序暴露），然后使用DAP，可显著增强体外活性。为了探索这些结果的基础，进行了蛋白质组学分析，有或没有β-内酰胺预处理。比较β-内酰胺预处理（与未处理对照）的相对蛋白质组学定量鉴定了几种众所周知的代谢、细胞和生物合成过程的差异调节，即，自溶和核黄素生物合成途径。此外，用β-内酰胺预处理的这些差异蛋白质组学读数不是PBP靶标特异性的。总之，这些研究表明，DAP-R MRSA中对β-内酰胺预处理的细胞反应导致蛋白质组中明显而复杂的变化，这些变化似乎使这些菌株对DAP介导的杀伤重新敏感。
Clinical treatment options for daptomycin (DAP)-resistant (DAP-R), methicillin-resistant Staphylococcus aureus (MRSA) infections are relatively limited. Current therapeutic strategies often take advantage of potential synergistic activity of DAP plus β-lactams; however, the mechanisms underlying their combinatorial efficacy are likely complex and remain incompletely understood. We recently showed thatin vitroβ-lactam passaging can resensitize DAP-R strains to a DAP-susceptible (DAP-S) phenotype. To further investigate the implications of selected β-lactam pretreatments on DAP plus β-lactam combination efficacy, we utilized DAP-R strain D712. We studied six such combinations, featuring β-lactams with a broad range of penicillin-binding protein-targeting profiles (PBP-1 to -4), using DAP-R strain D712. Of note, preconditioning with each β-lactam antibiotic (sequential exposures), followed by DAP exposure, yielded significantly enhancedin vitroactivity compared to either DAP treatment alone or simultaneous exposures to both antibiotics. To explore the underpinnings of these outcomes, proteomic analyses were performed, with or without β-lactam preconditioning. Relative proteomic quantitation comparing β-lactam pretreatments (versus untreated controls) identified differential modulation of several well-known metabolic, cellular, and biosynthetic processes, i.e., the autolytic and riboflavin biosynthetic pathways. Moreover, these differential proteomic readouts with β-lactam preconditioning were not PBP target specific. Taken together, these studies suggest that the cellular response to β-lactam preconditioning in DAP-R MRSA leads to distinct and complex changes in the proteome that appear to resensitize such strains to DAP-mediated killing.