Menaquinone biosynthesis potentiates haem toxicity in Staphylococcus aureus

Area of Science:

• Microbiology
• Pathogen Biology
• Bacterial Physiology

Background:

• Staphylococcus aureus is a versatile pathogen causing diverse diseases.
• Vertebrates sequester iron (heme) to limit pathogen growth.
• S. aureus utilizes high-affinity heme uptake systems but faces toxicity from excess heme.
• The HrtAB system in S. aureus is a known detoxification mechanism for heme stress.

Purpose of the Study:

• To identify the substrate transported by the HrtAB system.
• To elucidate the cellular factors contributing to heme toxicity in S. aureus.
• To understand the mechanism by which S. aureus overcomes heme stress.

Main Methods:

• A transposon screen was conducted in a heme-susceptible, HrtAB-deficient S. aureus strain.
• Identification of heme-resistant mutants to pinpoint factors involved in heme toxicity.
• Genetic analysis, including deletion of key genes in the menaquinone (MK) biosynthesis pathway.

Main Results:

• Transposon screen identified mutants with inactivated menaquinone (MK) biosynthesis pathway.
• Deletion of late-stage MK pathway genes confirmed their role in heme toxicity.
• Quinone molecules at the cell membrane potentiate heme-associated superoxide production and oxidative damage.
• A model was proposed involving a redox cycle between membrane-associated heme and quinones.

Conclusions:

• The menaquinone (MK) biosynthesis pathway is crucial for mediating heme toxicity in S. aureus.
• Membrane-associated quinones and heme form a redox cycle generating superoxide, leading to oxidative damage.
• Disrupting the MK pathway offers a potential strategy to combat S. aureus infections by mitigating heme toxicity.