The Journal of antimicrobial chemotherapy · 2025
The pivotal role of acnA in linking carbon metabolism to virulence and antimicrobial resistance in methicillin-resistant Staphylococcus aureus.
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Li Jiahui, Hou Wanwan, Chang Jiang, Tian Xiaorong, He Mu, Zhang Zengfeng, Shi Chunlei
Аннотация
BACKGROUND: Staphylococcus aureus, particularly MRSA strains, poses a critical global health threat due to its multidrug resistance and virulence.
OBJECTIVES: This study elucidates the role of the acnA gene, encoding aconitase in the tricarboxylic acid (TCA) cycle, in governing virulence and antimicrobial resistance in MRSA.
METHODS: The identification of the acnA mutant was performed by a transposon mutant library. The function of the acnA gene on virulence was evaluated through deletion and complementation analyses. Other phenotypes of ΔacnA were also determined, including growth curve, cell wall structure observations using scanning and transmission electron microscopy (SEM/TEM), cell wall thickness, autolysis and the determination of energy metabolism-associated phenotypes. MICs for BAA1717 and ΔacnA were determined by antimicrobial susceptibility testing. Finally, virulence- and resistance-related gene expression levels were determined by RT-qPCR.
RESULTS: Deletion of acnA in MRSA strain BAA1717 abolished staphyloxanthin biosynthesis and haemolytic activity, disrupted cell wall integrity and reduced resistance to β-lactams, aminoglycosides, macrolides and vancomycin, with MICs decreasing by 2- to 128-fold. Structural defects in the cell wall, visualized via SEM and TEM, correlated with heightened autolysis rates. Metabolic dysfunction in the acnA mutant was evident through diminished ATP production, NADPH synthesis and membrane potential. Transcriptional profiling revealed significant downregulation of virulence-related genes (crtO, crtP, hla, hlgA and hlyIII) and resistance determinants (sepA, norA, ftsW, pbps, murC and lytR).
CONCLUSIONS: These findings establish acnA as a metabolic nexus coordinating virulence and antimicrobial resistance in MRSA, highlighting its potential as a therapeutic target to disarm persistent infections through metabolic interference.
OBJECTIVES: This study elucidates the role of the acnA gene, encoding aconitase in the tricarboxylic acid (TCA) cycle, in governing virulence and antimicrobial resistance in MRSA.
METHODS: The identification of the acnA mutant was performed by a transposon mutant library. The function of the acnA gene on virulence was evaluated through deletion and complementation analyses. Other phenotypes of ΔacnA were also determined, including growth curve, cell wall structure observations using scanning and transmission electron microscopy (SEM/TEM), cell wall thickness, autolysis and the determination of energy metabolism-associated phenotypes. MICs for BAA1717 and ΔacnA were determined by antimicrobial susceptibility testing. Finally, virulence- and resistance-related gene expression levels were determined by RT-qPCR.
RESULTS: Deletion of acnA in MRSA strain BAA1717 abolished staphyloxanthin biosynthesis and haemolytic activity, disrupted cell wall integrity and reduced resistance to β-lactams, aminoglycosides, macrolides and vancomycin, with MICs decreasing by 2- to 128-fold. Structural defects in the cell wall, visualized via SEM and TEM, correlated with heightened autolysis rates. Metabolic dysfunction in the acnA mutant was evident through diminished ATP production, NADPH synthesis and membrane potential. Transcriptional profiling revealed significant downregulation of virulence-related genes (crtO, crtP, hla, hlgA and hlyIII) and resistance determinants (sepA, norA, ftsW, pbps, murC and lytR).
CONCLUSIONS: These findings establish acnA as a metabolic nexus coordinating virulence and antimicrobial resistance in MRSA, highlighting its potential as a therapeutic target to disarm persistent infections through metabolic interference.
Предметные рубрики MeSH
Methicillin-Resistant Staphylococcus aureusMicrobial Sensitivity TestsVirulenceAnti-Bacterial AgentsCell WallVirulence FactorsCarbonGene DeletionGene Expression ProfilingHumansGenetic Complementation TestStaphylococcal InfectionsMutagenesis, InsertionalDrug Resistance, BacterialMicroscopy, Electron, TransmissionCitric Acid CycleXanthophyllsBacterial Proteins