Impact of Bacterial Membrane Fatty Acid Composition on the Failure of Daptomycin To KillStaphylococcus aureus

ABSTRACTDaptomycin 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 againstStaphylococcus 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 againstS. aureusvaries 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 treatS. aureusis 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 restoreS. aureusdaptomycin bactericidal activityin vivocould open the way to novel antibiotic treatment strategies.

Download Full-text

Mutation of the NADH Oxidase Gene (nox) Reveals an Overlap of the Oxygen- and Acid-Mediated Stress Responses in Streptococcus mutans

Applied and Environmental Microbiology ◽

10.1128/aem.06890-11 ◽

2011 ◽

Vol 78 (4) ◽

pp. 1215-1227 ◽

Cited By ~ 29

Author(s):

Adam M. Derr ◽

Roberta C. Faustoferri ◽

Matthew J. Betzenhauser ◽

Kaisha Gonzalez ◽

Robert E. Marquis ◽

...

Keyword(s):

Fatty Acid Composition ◽

Fatty Acid ◽

Streptococcus Mutans ◽

Acid Composition ◽

Stress Responses ◽

Nadh Oxidase ◽

Membrane Fatty Acid ◽

Membrane Fatty Acid Composition ◽

Oxygen Stress ◽

Content Type

ABSTRACTNADH oxidase (Nox) is a flavin-containing enzyme used byStreptococcus mutansto reduce dissolved oxygen encountered during growth in the oral cavity. In this study, we characterized the role of the NADH oxidase in the oxidative and acid stress responses ofS. mutans. Anox-defective mutant strain ofS. mutansand its parental strain, the genomic type strain UA159, were exposed to various oxygen concentrations at pH values of 5 and 7 to better understand the adaptive mechanisms used by the organism to withstand environmental pressures. With the loss ofnox, the activities of oxygen stress response enzymes such as superoxide dismutase and glutathione oxidoreductase were elevated compared to those in controls, resulting in a greater adaptation to oxygen stress. In contrast, the loss ofnoxled to a decreased ability to grow in a low-pH environment despite an increased resistance to severe acid challenge. Analysis of the membrane fatty acid composition revealed that for both thenoxmutant and UA159 parent strain, growth in an oxygen-rich environment resulted in high proportions of unsaturated membrane fatty acids, independent of external pH. The data indicate thatS. mutansmembrane fatty acid composition is responsive to oxidative stress, as well as changes in environmental pH, as previously reported (E. M. Fozo and R. G. Quivey, Jr., Appl. Environ. Microbiol.70:929–936, 2004). The heightened ability of thenoxstrain to survive acidic and oxidative environmental stress suggests a multifaceted response system that is partially dependent on oxygen metabolites.

Download Full-text