Format

Send to

Choose Destination
Antimicrob Agents Chemother. 2019 Mar 27;63(4). pii: e02105-18. doi: 10.1128/AAC.02105-18. Print 2019 Apr.

A FASII Inhibitor Prevents Staphylococcal Evasion of Daptomycin by Inhibiting Phospholipid Decoy Production.

Author information

1
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom.
2
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom a.edwards@imperial.ac.uk.
#
Contributed equally

Abstract

Daptomycin is a treatment of last resort for serious infections caused by drug-resistant Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus We have shown recently that S. aureus can evade daptomycin by releasing phospholipid decoys that sequester and inactivate the antibiotic, leading to treatment failure. Since phospholipid release occurs via an active process, we hypothesized that it could be inhibited, thereby increasing daptomycin efficacy. To identify opportunities for therapeutic interventions that block phospholipid release, we first determined how the host environment influences the release of phospholipids and the inactivation of daptomycin by S. aureus The addition of certain host-associated fatty acids to the growth medium enhanced phospholipid release. However, in serum, the sequestration of fatty acids by albumin restricted their availability to S. aureus sufficiently to prevent their use in the generation of released phospholipids. This finding implies that in host tissues S. aureus may be completely dependent upon endogenous phospholipid biosynthesis to generate lipids for release, providing a target for therapeutic intervention. To test this, we exposed S. aureus to AFN-1252, an inhibitor of the staphylococcal FASII fatty acid biosynthetic pathway, together with daptomycin. AFN-1252 efficiently blocked daptomycin-induced phospholipid decoy production, even in the case of isolates resistant to AFN-1252, which prevented the inactivation of daptomycin and resulted in sustained bacterial killing. In turn, daptomycin prevented the fatty acid-dependent emergence of AFN-1252-resistant isolates in vitro In summary, AFN-1252 significantly enhances daptomycin activity against S. aureus in vitro by blocking the production of phospholipid decoys, while daptomycin blocks the emergence of resistance to AFN-1252.

KEYWORDS:

AFN-1252; Staphylococcus aureus ; antibiotic resistance; daptomycin; experimental therapeutics; phospholipids

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center