CREM, Department of Life Sciences, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal.
PLoS Pathog. 2012;8(7):e1002816. doi: 10.1371/journal.ppat.1002816. Epub 2012 Jul 26.
Methicillin-resistant Staphylococcus aureus (MRSA) is an important human pathogen, which is cross-resistant to virtually all β-lactam antibiotics. MRSA strains are defined by the presence of mecA gene. The transcription of mecA can be regulated by a sensor-inducer (MecR1) and a repressor (MecI), involving a unique series of proteolytic steps. The induction of mecA by MecR1 has been described as very inefficient and, as such, it is believed that optimal expression of β-lactam resistance by MRSA requires a non-functional MecR1-MecI system. However, in a recent study, no correlation was found between the presence of functional MecR1-MecI and the level of β-lactam resistance in a representative collection of epidemic MRSA strains. Here, we demonstrate that the mecA regulatory locus consists, in fact, of an unusual three-component arrangement containing, in addition to mecR1-mecI, the up to now unrecognized mecR2 gene coding for an anti-repressor. The MecR2 function is essential for the full induction of mecA expression, compensating for the inefficient induction of mecA by MecR1 and enabling optimal expression of β-lactam resistance in MRSA strains with functional mecR1-mecI regulatory genes. Our data shows that MecR2 interacts directly with MecI, destabilizing its binding to the mecA promoter, which results in the repressor inactivation by proteolytic cleavage, presumably mediated by native cytoplasmatic proteases. These observations point to a revision of the current model for the transcriptional control of mecA and open new avenues for the design of alternative therapeutic strategies for the treatment of MRSA infections. Moreover, these findings also provide important insights into the complex evolutionary pathways of antibiotic resistance and molecular mechanisms of transcriptional regulation in bacteria.
耐甲氧西林金黄色葡萄球菌（MRSA）是一种重要的人类病原体，对几乎所有β-内酰胺类抗生素都具有交叉耐药性。MRSA 菌株的定义是存在 mecA 基因。mecA 的转录可以被传感器诱导物（MecR1）和抑制剂（MecI）调节，涉及到一系列独特的蛋白水解步骤。MecR1 对 mecA 的诱导被描述为非常低效，因此，人们认为 MRSA 对β-内酰胺类抗生素的最佳表达需要一个无功能的 MecR1-MecI 系统。然而，在最近的一项研究中，在一组具有代表性的流行 MRSA 菌株中，没有发现功能性 MecR1-MecI 的存在与β-内酰胺类抗生素耐药水平之间存在相关性。在这里，我们证明 mecA 调节基因座实际上由一个不寻常的三组分排列组成，除了 mecR1-mecI 之外，还包含了迄今为止未被识别的 mecR2 基因，该基因编码一个反抑制剂。MecR2 功能对于 mecA 表达的完全诱导是必不可少的，它补偿了 MecR1 对 mecA 诱导的低效性，并使功能性 mecR1-mecI 调节基因的 MRSA 菌株能够最佳地表达β-内酰胺类抗生素耐药性。我们的数据表明，MecR2 与 MecI 直接相互作用，使其不稳定，从而导致其与 mecA 启动子的结合被蛋白酶切割失活，推测是由天然细胞质蛋白酶介导的。这些观察结果表明，需要对 mecA 的转录控制的当前模型进行修订，并为治疗 MRSA 感染的替代治疗策略的设计开辟新的途径。此外，这些发现还为抗生素耐药性的复杂进化途径和细菌转录调控的分子机制提供了重要的见解。
