Impact of Bacterial Membrane Fatty Acid Composition on the Failure of Daptomycin To Kill Staphylococcus aureus
Rym Boudjemaa1, Clément Cabriel2, Florence Dubois-Brissonnet3
1Institut des Sciences Moléculaires d'Orsay (ISMO), CNRS, Université Paris-Sud, Université Paris-Saclay, Orsay, France rymboudjemaa@gmail.com.
Abstract:
Daptomycin is a last-resort membrane-targeting lipopeptide approved for the treatment of drug-resistant staphylococcal infections, such as bacteremia and implant-related infections. Although cases of resistance to this antibiotic are rare, increasing numbers of clinical, in vitro, and animal studies report treatment failure, notably against Staphylococcus aureus The aim of this study was to identify the features of daptomycin and its target bacteria that lead to daptomycin treatment failure. We show that daptomycin bactericidal activity against S. aureus varies significantly with the growth state and strain, according to the membrane fatty acid composition. Daptomycin efficacy as an antibiotic relies on its ability to oligomerize within membranes and form pores that subsequently lead to cell death. Our findings ascertain that daptomycin interacts with tolerant bacteria and reaches its membrane target, regardless of its bactericidal activity. However, the final step of pore formation does not occur in cells that are daptomycin tolerant, strongly suggesting that it is incapable of oligomerization. Importantly, membrane fatty acid contents correlated with poor daptomycin bactericidal activity, which could be manipulated by fatty acid addition. In conclusion, daptomycin failure to treat S. aureus is not due to a lack of antibiotic-target interaction, but is driven by its capacity to form pores, which depends on membrane composition. Manipulation of membrane fluidity to restore S. aureus daptomycin bactericidal activity in vivo could open the way to novel antibiotic treatment strategies.
Insights
Daptomycin treatment failure against Staphylococcus aureus is not due to lack of target interaction but pore formation issues. Membrane fatty acid composition influences daptomycin
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Daptomycin is a critical antibiotic for drug-resistant staphylococcal infections.
- Treatment failures with daptomycin, particularly against Staphylococcus aureus, are increasingly reported.
- Understanding daptomycin resistance mechanisms is crucial for effective treatment.
Purpose of the Study:
- To identify factors contributing to daptomycin treatment failure in Staphylococcus aureus.
- To investigate the relationship between bacterial membrane properties and daptomycin efficacy.
- To elucidate the mechanism of daptomycin tolerance.
Main Methods:
- Assessing daptomycin bactericidal activity across different Staphylococcus aureus growth states and strains.
- Analyzing the correlation between membrane fatty acid composition and daptomycin efficacy.
- Investigating daptomycin-target interaction and pore formation in tolerant bacteria.
Main Results:
- Daptomycin's activity against Staphylococcus aureus is highly dependent on bacterial growth state and membrane fatty acid composition.
- Daptomycin successfully interacts with tolerant bacteria but fails to form pores, indicating an oligomerization defect.
- Altering membrane fatty acid content can modulate daptomycin's bactericidal activity.
Conclusions:
- Daptomycin treatment failure is linked to impaired pore formation, not antibiotic-target interaction.
- Bacterial membrane composition is a key determinant of daptomycin efficacy.
- Manipulating membrane fluidity offers a potential strategy to overcome daptomycin resistance.
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