Host Fatty Acid Utilization by Staphylococcus aureus at the Infection Site

Area of Science:

• Microbiology
• Molecular Biology
• Biochemistry

Background:

• Staphylococcus aureus infections pose a significant threat due to rising antibiotic resistance.
• Fatty acid (FA) synthesis inhibitors are a promising therapeutic strategy, but their efficacy may be limited if S. aureus can utilize host FAs.
• Understanding S. aureus membrane synthesis is crucial for developing effective treatments.

Purpose of the Study:

• To investigate how S. aureus synthesizes its membrane phospholipids at the infection site.
• To determine the role of host-derived FAs versus de novo FA synthesis in S. aureus membrane construction.
• To assess the impact of FA assimilation on S. aureus virulence and susceptibility to FA synthesis inhibitors.

Main Methods:

• Development of a lipidomics workflow using mass spectrometry to analyze S. aureus membrane composition.
• Infection of mice with wild-type and mutant S. aureus strains lacking key FA activation enzymes (FakA, FakB1, FakB2).
• Analysis of FA profiles in S. aureus grown in vitro and recovered from thigh infection sites.

Main Results:

• S. aureus utilizes host FAs (palmitate, oleate) and de novo synthesized pentadecanoic acid for phosphatidylglycerol (PG) synthesis.
• Mutants unable to assimilate host FAs were attenuated in a mouse thigh infection model.
• S. aureus membrane composition shifted towards even-chain FAs and away from branched-chain FAs during infection.
• Pentadecanoic acid, derived from isoleucine, is essential and cannot be fully replaced by host FAs.

Conclusions:

• S. aureus actively incorporates host FAs into its membrane but maintains a critical requirement for de novo FA synthesis.
• The inability to acquire sufficient isoleucine at the infection site necessitates pentadecanoic acid production.
• This reliance on internal FA synthesis validates the therapeutic potential of targeting FA synthesis pathways in S. aureus.