2. Academic Validation
  3. Alisol A 24-Acetate combats Methicillin-Resistant Staphylococcus aureus infection by targeting the mevalonate biosynthesis

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

  • Biochem Pharmacol. 2025 Mar:233:116766. doi: 10.1016/j.bcp.2025.116766.
Li-Jie Liang 1,  Bing He 1,  Yin Liang 2,  Yu-Ze Li 2,  Ze-Miao Li 2,  Rui-Bing Liu 2,  Ting-Ting Zhu 2,  Yang Luo 2,  Xin-Lei Lian 2,  Dong-Hao Zhao 2,  Jian Sun 3,  Hao Ren 4,  Xiao-Ping Liao 5
Affiliations

Affiliations

  • 1 Institute of Animal Husbandry and Veterinary Medicine, Fujian Academy of Agricultural Sciences, Fuzhou 350013, China; Guangdong Laboratory for Lingnan Modern Agriculture, National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics, Development and Safety Evaluation, South China Agricultural University, Guangzhou 510642, China.
  • 2 Guangdong Laboratory for Lingnan Modern Agriculture, National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics, Development and Safety Evaluation, South China Agricultural University, Guangzhou 510642, China.
  • 3 State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics, Development and Safety Evaluation, South China Agricultural University, Guangzhou 510642, China; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.
  • 4 State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China. Electronic address: [email protected].
  • 5 Guangdong Laboratory for Lingnan Modern Agriculture, National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics, Development and Safety Evaluation, South China Agricultural University, Guangzhou 510642, China. Electronic address: [email protected].
PMID: 39894304 DOI: 10.1016/j.bcp.2025.116766
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.

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