Natural lipopeptide antibiotic tripropeptin C (TPPC) revitalizes and synergistically potentiates the activities of the class of β-lactam antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) but not against methicillin-sensitive S. aureus in vitro; however, the mode of action remains unclear. In the course of the study to reveal its mode of action, we found that TPPC inhibited the β-lactamase production induced by cefotiam. This prompted us to focus on the β-lactam-inducible β-lactam-resistant genes blaZ (β-lactamase) and mecA (foreign penicillin-binding protein), as they are mutually regulated by the blaZ/I/R1 and mecA/I/R1 systems. Quantitative reverse-transcription polymerase chain reaction analysis revealed that TPPC reversed β-lactam resistance by reducing the expression of the genes blaZ and mecA, when treated alone or in combination with β-lactam antibiotics. In a mouse/MRSA septicemia model, subcutaneous injection of a combination of TPPC and ceftizoxime demonstrated synergistic therapeutic efficacy compared with each drug alone. These observations strongly suggested that reverse β-lactam resistance by TPPC may be a potentially effective new therapeutic strategy to overcome refractory MRSA infections.The Journal of Antibiotics advance online publication, 26 July 2017; doi:10.1038/ja.2017.88.

中文翻译：

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β-内酰胺/三丙肽C在小鼠败血症模型中的体内功效以及三丙肽C介导的耐甲氧西林金黄色葡萄球菌逆转β-内酰胺耐药的机制。


天然脂肽抗生素三丙肽 C (TPPC) 可恢复并协同增强 β-内酰胺类抗生素对耐甲氧西林金黄色葡萄球菌 (MRSA) 的活性，但对体外对甲氧西林敏感的金黄色葡萄球菌没有作用；然而，行动方式仍不清楚。在揭示其作用机制的研究过程中，我们发现TPPC抑制头孢替安诱导的β-内酰胺酶的产生。这促使我们关注β-内酰胺诱导的β-内酰胺抗性基因blaZ（β-内酰胺酶）和mecA（外来青霉素结合蛋白），因为它们受到blaZ/I/R1和mecA/I的相互调节/R1系统。定量逆转录聚合酶链反应分析表明，单独治疗或与 β-内酰胺抗生素联合治疗时，TPPC 通过降低 blaZ 和 mecA 基因的表达来逆转 β-内酰胺耐药性。在小鼠/MRSA败血症模型中，与单独使用每种药物相比，皮下注射TPPC和头孢唑肟组合显示出协同治疗功效。这些观察结果强烈表明，通过 TPPC 逆转 β-内酰胺耐药性可能是克服难治性 MRSA 感染的潜在有效的新治疗策略。《抗生素杂志》高级在线出版，2017 年 7 月 26 日； doi：10.1038/ja.2017.88。