Accumulation of Succinyl Coenzyme A Perturbs the Methicillin-Resistant Staphylococcus aureus (MRSA) Succinylome and Is Associated with Increased Susceptibility to Beta-Lactam Antibiotics.
Accumulation of Succinyl Coenzyme A Perturbs the Methicillin-Resistant Staphylococcus aureus (MRSA) Succinylome and Is Associated with Increased Susceptibility to Beta-Lactam Antibiotics.
复制标题
琥珀酰辅酶A的积累使甲氧西林抗葡萄球菌金黄色葡萄球菌（MRSA）琥珀酰基琥珀酰基琥珀酰基琥珀酰基琥珀酰基琥珀酸酯菌，与β-内酰胺抗生素的易感性增加有关。
DOI：
10.1128/mbio.00530-21
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发表时间：
2021-06-29
期刊：
影响因子：
6.4
通讯作者：
O'Gara JP
中科院分区：
文献类型：
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作者：
Campbell C;Fingleton C;Zeden MS;Bueno E;Gallagher LA;Shinde D;Ahn J;Olson HM;Fillmore TL;Adkins JN;Razvi F;Bayles KW;Fey PD;Thomas VC;Cava F;Clair GC;O'Gara JP
耐甲氧西林金黄色葡萄球菌 (MRSA) 中的青霉素结合蛋白 2a (PBP2a) 依赖性对 β-内酰胺类抗生素的耐药性是通过三羧酸 (TCA) 循环的活性通过一种鲜为人知的机制来调节的。我们报告说，sucC 和 sucD 的突变（而不是其他 TCA 循环酶）会对 β-内酰胺耐药性产生负面影响，但不会改变 PBP2a 的表达。 sucC 突变体中琥珀酰辅酶 A (琥珀酰-CoA) 细胞内水平的增加显着扰乱了 MRSA 蛋白质组中的赖氨酸琥珀酰化。负责琥珀酰辅酶A生物合成的sucA或sucB中的抑制突变逆转了sucC突变表型。主要自溶素 (Atl) 是蛋白质组中琥珀酰化程度最高的蛋白质，sucC 突变体中 Atl 琥珀酰化程度的增加与自溶活性的丧失相关。尽管 PBP2a 和 PBP2 也是 MRSA 蛋白质组中琥珀酰化程度最高的蛋白质之一，但 sucC 突变体中的肽聚糖结构和交联没有变化。这些数据表明，MRSA 琥珀酰组的扰动会影响两个相互关联的细胞壁表型，导致自溶活性受到抑制并增加对 β-内酰胺抗生素的敏感性。
Penicillin binding protein 2a (PBP2a)-dependent resistance to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) is regulated by the activity of the tricarboxylic acid (TCA) cycle via a poorly understood mechanism. We report that mutations in sucC and sucD, but not other TCA cycle enzymes, negatively impact β-lactam resistance without changing PBP2a expression. Increased intracellular levels of succinyl coenzyme A (succinyl-CoA) in the sucC mutant significantly perturbed lysine succinylation in the MRSA proteome. Suppressor mutations in sucA or sucB, responsible for succinyl-CoA biosynthesis, reversed sucC mutant phenotypes. The major autolysin (Atl) was the most succinylated protein in the proteome, and increased Atl succinylation in the sucC mutant was associated with loss of autolytic activity. Although PBP2a and PBP2 were also among the most succinylated proteins in the MRSA proteome, peptidoglycan architecture and cross-linking were unchanged in the sucC mutant. These data reveal that perturbation of the MRSA succinylome impacts two interconnected cell wall phenotypes, leading to repression of autolytic activity and increased susceptibility to β-lactam antibiotics.