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Title: Identification and characterisation of a novel mechanism of antibiotic resistance
Author: Pader, Vera Aspi
ISNI:       0000 0004 6496 9435
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Daptomycin is a bactericidal antibiotic of last resort for serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Although resistance is rare, treatment failure can occur in >20% of cases and so there is a pressing need to identify and mitigate factors that contribute to poor therapeutic outcomes. Work described in this thesis revealed that loss of the Agr quorum-sensing system, which frequently occurs in clinical isolates, enhanced 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 phospholipid, 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 release by S. aureus occurred via an active process that appears to involve the VraUTRS regulon, and was inhibited by the β-lactam antibiotic oxacillin, which slowed inactivation of daptomycin and enhanced bacterial killing. Subsequent work revealed that next-generation lipid biosynthesis inhibitors completely blocked phospholipid release, whilst the presence of host-associated fatty acids enhanced the release of membrane phospholipids. Future work will determine the molecular mechanism by which S. aureus releases phospholipids, and exploit this information to develop new therapeutic approaches that enhance daptomycin treatment efficacy.
Supervisor: Edwards, Andrew M. ; Wigneshweraraj, Shivaramesh Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral