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Vera Pader1, Sanika Hakim1, Kimberley L Painter1
1MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
Abstract:
Daptomycin is a bactericidal antibiotic of last resort for serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA)1,2. Although resistance is rare, treatment failure can occur in more than 20% of cases3,4 and so there is a pressing need to identify and mitigate factors that contribute to poor therapeutic outcomes. Here, we show that loss of the Agr quorum-sensing system, which frequently occurs in clinical isolates, enhances S. aureus survival during daptomycin treatment. Wild-type S. aureus was killed rapidly by daptomycin, but Agr-defective mutants survived antibiotic exposure by releasing membrane phospholipids, which bound and inactivated the antibiotic. Although wild-type bacteria also released phospholipid in response to daptomycin, Agr-triggered secretion of small cytolytic toxins, known as phenol soluble modulins, prevented antibiotic inactivation. Phospholipid shedding by S. aureus occurred via an active process and was inhibited by the β-lactam antibiotic oxacillin, which slowed inactivation of daptomycin and enhanced bacterial killing. In conclusion, S. aureus possesses a transient defence mechanism that protects against daptomycin, which can be compromised by Agr-triggered toxin production or an existing therapeutic antibiotic.
Insights
Agr-defective Staphylococcus aureus survives daptomycin treatment by releasing membrane phospholipids that inactivate the antibiotic. This defense mechanism is overcome by phenol soluble modulin toxins or oxacillin, enhancing daptomycin
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.
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