Metabolic reprogramming promotes Staphylococcus aureus serum resistance

Area of Science:

• Microbiology and Infectious Diseases
• Molecular Biology
• Genomics

Background:

• Staphylococcus aureus bloodstream infections cause significant mortality worldwide.
• Previous functional genomics identified polygenic adaptation to human serum.
• A specific mutation (V76I) in dihydrolipoamide dehydrogenase (PdhD) enhances S. aureus survival.

Purpose of the Study:

• To elucidate the mechanisms by which the PdhD V76I mutation improves S. aureus survival in human serum.
• To investigate the role of enhanced antimicrobial resistance and metabolic activity in host adaptation.

Main Methods:

• Functional genomics and strain characterization.
• Measurement of diaphorase activity and NADH/NAD+ recycling.
• Assessment of bacterial resistance to host-derived antimicrobials (e.g., LL37, fatty acids) and antibiotics (e.g., gentamicin).
• Analysis of bacterial growth, membrane potential, and metabolic pathways (glycolysis, TCA cycle) in human serum.

Main Results:

• The PdhD V76I variant exhibits enhanced diaphorase activity, facilitating NADH recycling and decreasing membrane potential.
• Strains expressing PdhD V76I show increased resistance to antimicrobial peptides, fatty acids, gentamicin, and hydrogen peroxide.
• This mutation enhances glycolysis and TCA cycle activity, promoting bacterial replication in serum without typical persister/SCV phenotypes.

Conclusions:

• The PdhD V76I mutation confers enhanced survival in the bloodstream by improving resistance to host defenses and boosting metabolic activity.
• This study reveals intermediate adaptation phenotypes contributing to S. aureus survival in hostile host environments.
• Understanding these host adaptation mechanisms is crucial for developing novel therapeutics targeting S. aureus infections.