Alisol A 24-Acetate combats Methicillin-Resistant Staphylococcus aureus infection by targeting the mevalonate biosynthesis

Abstract

Infections caused by Methicillin-resistant Staphylococcus aureus (MRSA) have emerged as one of the most pressing global public health challenges. In concert with global rise of antimicrobial resistance at alarming rate, there is an urgent need for alternative strategies to combat MRSA. Here, the high throughput screening indicated that the Alisol A 24-acetate (AA) effectively inhibits the mevalonate (MVA) synthesis in MRSA. The mechanistic analysis revealed that AA competitively inhibits the 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) protein to blockade the MVA pathway, thereby disrupting the bacterial membrane integrity and functions. Further investigations showed that this disruption consequently restores the β-lactam susceptibility in MRSA by retarding the expression of PBP2a protein and dampens the virulence of MRSA by reducing the exotoxins secretion. In addition to the effect on MRSA, AA has been found to exert host-acting activity to reduce the MRSA-induced inflammation. The promising anti-MRSA activity of AA was further confirmed in vivo. Collectively, the current study highlighted the potential of AA as a proposing drug for combating MRSA and emphasize the MVA pathway as an ideal therapeutic target for MRSA treatment.

Keywords: Alisol A 24-acetate (AA); Host immune responses; Membrane physiology; Methicillin-resistant Staphylococcus aureus (MRSA); Mevalonate (MVA) biosynthesis.