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Varied Contribution of Phospholipid Shedding From Membrane to Daptomycin Tolerance in Staphylococcus aureus
- Source :
- Frontiers in Molecular Biosciences, Frontiers in Molecular Biosciences, Vol 8 (2021)
- Publication Year :
- 2021
- Publisher :
- Frontiers Media SA, 2021.
-
Abstract
- It has been suggested that daptomycin can be inactivated by lipids released by Staphylococcus aureus and that this effect is antagonized by phenol soluble modulins (PSMs), which bind to the shed lipids. PSM production is regulated by the Agr system, and others have shown that loss of the Agr function enhances S. aureus survival in the presence of daptomycin. Here we assessed the impact of Agr function on daptomycin activity and lipid metabolism under various conditions. Daptomycin activity was evaluated against three sets of isogenic strain series with wild-type or dysfunctional Agr using static daptomycin time-kills over 24 h and against one strain pair using in vitro pharmacokinetic/pharmacodynamic (PK/PD) models simulating clinical daptomycin exposure for 48 h. We performed comprehensive lipidomics on bacterial membranes and the spent media to correlate lipid shedding with survival. In static time-kill experiments, two agr-deficient strains (SH1000- and USA300 LAC ΔagrA) showed improved survival for 8 h compared with their corresponding wild-type strains as seen in previous studies, but this difference did not persist for 24 h. However, four other agr-deficient strains (SH1001 and JE2 agr KOs) did not demonstrate improved survival compared to isogenic wild-type strains at any time in the time-kills. Lipidomics analysis of SH1000, SH1001, and SH1000- strains showed daptomycin exposure increased lipid shedding compared to growth controls in all strains with phosphatidylglycerols (PGs), lysylPGs and cardiolipins predominating. In the cell pellets, PGs and lysylPGs decreased but cardiolipins were unchanged with daptomycin exposure. The shed lipid profiles in SH1001 and SH1000- were similar, suggesting that the inability to resist daptomycin by SH1001 was not because of differences in lipid shedding. In the PK/PD model, the agr mutant SH1000- strain did not show improved survival relative to SH1000 either. In conclusion, inactivation of daptomycin by shed lipids may be dependent on genetic background, the specific agr mutations, or the techniques used to generate these KOs rather than the overall function of the Agr system, and its contribution to daptomycin tolerance seems to be varied, transient, and growth-condition dependent.
- Subjects :
- 0301 basic medicine
QH301-705.5
030106 microbiology
Mutant
Phospholipid
medicine.disease_cause
Biochemistry, Genetics and Molecular Biology (miscellaneous)
Biochemistry
Microbiology
03 medical and health sciences
chemistry.chemical_compound
Lipidomics
medicine
Molecular Biosciences
Biology (General)
Molecular Biology
Original Research
phospholipid release
Strain (chemistry)
Chemistry
Agr
Lipid metabolism
biochemical phenomena, metabolism, and nutrition
bacterial infections and mycoses
pharmacokinetic and pharmacodynamic model
In vitro
030104 developmental biology
Staphylococcus aureus
lipidomics
daptomycin tolerance
lipids (amino acids, peptides, and proteins)
Daptomycin
medicine.drug
Subjects
Details
- ISSN :
- 2296889X
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Frontiers in Molecular Biosciences
- Accession number :
- edsair.doi.dedup.....437bbedfcceb2a4a1192baf03aaa49c1