Staphylococcus aureus inactivates daptomycin by releasing membrane phospholipids.

Area of Science:

• Microbiology
• Infectious Diseases
• Antibiotic Resistance

Background:

• Daptomycin is a critical last-resort antibiotic for treating serious methicillin-resistant Staphylococcus aureus (MRSA) infections.
• Treatment failures with daptomycin occur in over 20% of cases, necessitating identification of factors contributing to poor outcomes.
• The Agr quorum-sensing system is frequently lost in clinical Staphylococcus aureus isolates.

Purpose of the Study:

• To investigate the role of the Agr quorum-sensing system in Staphylococcus aureus survival during daptomycin treatment.
• To elucidate the mechanisms by which Agr-defective mutants evade daptomycin.
• To identify factors that can mitigate daptomycin efficacy.

Main Methods:

• Comparison of daptomycin killing kinetics between wild-type and Agr-defective Staphylococcus aureus.
• Analysis of phospholipid release and antibiotic inactivation in response to daptomycin.
• Investigation of the role of phenol soluble modulins (PSMs) in daptomycin resistance.
• Assessment of oxacillin's effect on daptomycin inactivation and bacterial killing.

Main Results:

• Agr-defective Staphylococcus aureus mutants exhibited enhanced survival against daptomycin compared to wild-type.
• Survival was mediated by the release of membrane phospholipids that bound and inactivated daptomycin.
• Agr-triggered PSM toxins in wild-type bacteria prevented phospholipid-mediated antibiotic inactivation.
• Oxacillin inhibited phospholipid shedding, slowed daptomycin inactivation, and enhanced bacterial killing.

Conclusions:

• Loss of the Agr quorum-sensing system confers a survival advantage to Staphylococcus aureus during daptomycin therapy.
• Staphylococcus aureus employs a transient defense mechanism involving phospholipid shedding against daptomycin.
• This defense can be compromised by Agr-mediated toxin production or co-administration of certain antibiotics like oxacillin.