Occurrence of cross-resistance and β-lactam seesaw effect in glycopeptide-, lipopeptide- and lipoglycopeptide-resistant MRSA correlates with membrane phosphatidylglycerol levels
Occurrence of cross-resistance and β-lactam seesaw effect in glycopeptide-, lipopeptide- and lipoglycopeptide-resistant MRSA correlates with membrane phosphatidylglycerol levels
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DOI：
10.1093/jac/dkz562
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发表时间：
2020-05-01
影响因子：
5.2
通讯作者：
Xu, Libin
中科院分区：
文献类型：
--
作者：
Hines, Kelly M.;Shen, Tianwei;Xu, Libin
背景：糖肽（GP）、脂肽（LP）和脂糖肽（LGP）是相关的抗菌药物，对于治疗侵袭性 MRSA 感染非常重要。 MRSA 中这些抗生素之间的交叉耐药性已得到充分记录，并且观察到 MRSA 对 β-内酰胺类药物的敏感性随着对 GP 和 LP 敏感性的降低而增加（即跷跷板效应）。了解 GP/LP/LGP 交叉耐药性与跷跷板效应之间关系的努力主要集中在 PBP 上，但尚未研究脂质代谢的作用。 目的：由于细胞膜在结构和代谢上与细胞壁和锚定相关蛋白（包括 PBP）整合在一起，因此我们研究了膜脂组成与 PBP 之间交叉耐药现象之间的关系。 GPs/LPs/LGPs 和 β-内酰胺跷跷板效应。方法：我们使用 USA300 菌株 JE2 选择达托霉素、万古霉素和达巴万星耐药性，并通过全基因组测序、基于 MS 的脂质组学和抗菌药敏测试评估所得突变体，以评估膜成分、交叉耐药性和跷跷板效应之间的关系。结果： 我们观察到所选菌株对 GPs/LPs/LGPs 的交叉耐药性以及对各种 β-内酰胺的跷跷板效应，具体取决于特定 β-内酰胺的 PBP 靶标。我们发现膜组成的改变不仅发生在达托霉素选择的菌株中，而且也发生在万古霉素和达巴万星选择的菌株中。值得注意的是，我们观察到大多数磷脂酰甘油的丰度与 GP/LP/LGP 的 MIC 呈正相关，与 β-内酰胺的 MIC 呈负相关。结论：这些研究表明膜重塑、交叉耐药和跷跷板效应之间存在主要关联。
Background: Glycopeptides (GPs), lipopeptides (LPs) and lipoglycopeptides (LGPs) are related antimicrobials important for the management of invasive MRSA infections. Cross-resistance among these antibiotics in MRSA is well documented, as is the observation that susceptibility of MRSA to beta-lactams increases as susceptibility to GPs and LPs decreases (i.e. the seesaw effect). Efforts to understand the relationship between GP/LP/LGP cross-resistance and the seesaw effect have focused on the PBPs, but the role of lipid metabolism has not been investigated.Objectives: Since the cell membrane is structurally and metabolically integrated with the cell wall and anchors associated proteins, including PBPs, we examined the relationship between membrane lipid composition and the phenomena of cross-resistance among GPs/LPs/LGPs and the beta-lactam seesaw effect.Methods: We selected for daptomycin, vancomycin and dalbavancin resistance using the USA300 strain JE2 and evaluated the resulting mutants by WGS, MS-based lipidomics and antimicrobial susceptibility testing to assess the relationship between membrane composition, cross-resistance, and the seesaw effect.Results: We observed cross-resistance to GPs/LPs/LGPs among the selected strains and the seesaw effect against various beta-lactams, depending on the PBP targets of the particular beta-lactam. We found that modification of membrane composition occurs not only in daptomycin-selected strains, but also vancomycin- and dalbavancin-selected strains. Significantly, we observed that the abundance of most phosphatidylglycerols positively correlates with MICs of GPs/LPs/LGPs and negatively correlates with the MICs of beta-lactams.Conclusions: These studies demonstrate a major association between membrane remodelling, cross-resistance and the seesaw effect.