金黄色葡萄球菌
微生物学
抗生素
内酰胺
调节器
抗生素耐药性
耐甲氧西林金黄色葡萄球菌
β-内酰胺
生物
细菌
化学
遗传学
立体化学
基因
作者
Tobias Krogh Nielsen,Irene Petersen,Lijuan Xu,Maria Disen Barbuti,Viktor Hundtofte Mebus,Anni Justh,Abdulelah A Alqarzaee,Nicolas Jacques,Cécile Oury,Vinai C. Thomas,Morten Kjos,Camilla Henriksen,Dorte Frees
摘要
ABSTRACT Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a leading cause of mortality worldwide. MRSA has acquired resistance to next-generation β-lactam antibiotics through the horizontal acquisition of the mecA resistance gene. Development of high resistance is, however, often associated with additional mutations in a set of chromosomal core genes, known as potentiators, which, through poorly described mechanisms, enhance resistance. The yjbH gene was recently identified as a hot spot for adaptive mutations during severe infections. Here, we show that inactivation of yjbH increased β-lactam MICs up to 16-fold and transformed MRSA cells with low levels of resistance to being homogenously highly resistant to β-lactams. The yjbH gene encodes an adaptor protein that targets the transcriptional stress regulator Spx for degradation by the ClpXP protease. Using CRISPR interference (CRISPRi) to knock down spx transcription, we unambiguously linked hyper-resistance to the accumulation of Spx. Spx was previously proposed to be essential; however, our data suggest that Spx is dispensable for growth at 37°C but becomes essential in the presence of antibiotics with various targets. On the other hand, high Spx levels bypassed the role of PBP4 in β-lactam resistance and broadly decreased MRSA susceptibility to compounds targeting the cell wall or the cell membrane, including vancomycin, daptomycin, and nisin. Strikingly, Spx potentiated resistance independently of its redox-sensing switch. Collectively, our study identifies a general stress pathway that, in addition to promoting the development of high-level, broad-spectrum β-lactam resistance, also decreases MRSA susceptibility to critical antibiotics of last resort.
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