title: Staphylococcus aureus inactivates daptomycin by releasing membrane phospholipids.
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 cases3,4and 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.
authors: MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
authors: Vera
authors: V
authors: Pader
authors: MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
authors: Sanika
authors: S
authors: Hakim
authors: MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
authors: Kimberley L
authors: KL
authors: Painter
authors: MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
authors: Sivaramesh
authors: S
authors: Wigneshweraraj
authors: MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
authors: Thomas B
authors: TB
authors: Clarke
authors: MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
authors: Andrew M
authors: AM
authors: Edwards
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001426:Bacterial Proteins; D002462:Cell Membrane / Q000187:drug effects*; D017576:Daptomycin / Q000378:metabolism*; D004361:Drug Tolerance; D050296:Microbial Viability / Q000187:drug effects; D010743:Phospholipids / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics; D015534:Trans-Activators / Q000172:deficiency
chemical_list: C095698:Agr protein, Staphylococcus aureus; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010743:Phospholipids; D015534:Trans-Activators; D017576:Daptomycin