@article{Tickle:2022:10.1101/2022.10.12.511873,
author = {Tickle, ARH and Ledger, EVK and Edwards, AM},
doi = {10.1101/2022.10.12.511873},
title = {Human serum induces daptomycin tolerance in<i>Enterococcus faecalis</i>and viridans group streptococci},
url = {http://dx.doi.org/10.1101/2022.10.12.511873},
year = {2022}
}

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TY  - JOUR
AB  - <jats:title>Abstract</jats:title><jats:p>Daptomycin is a membrane-targeting lipopeptide antibiotic used in the treatment of infective endocarditis caused by multidrug-resistant Gram-positive bacteria such as<jats:italic>Staphylococcus aureus</jats:italic>, enterococci and viridans group streptococci. Despite demonstrating excellent<jats:italic>in vitro</jats:italic>activity and a low prevalence of resistant isolates, treatment failure is a significant concern, particularly for enterococcal infection. We have shown recently that human serum triggers daptomycin tolerance in<jats:italic>S. aureus</jats:italic>, but it was not clear if a similar phenotype occurred in other major infective endocarditis pathogens. We found that<jats:italic>Enterococcus faecalis, Streptococcus gordonii</jats:italic>or<jats:italic>Streptococcus mutans</jats:italic>grown under standard laboratory conditions were efficiently killed by daptomycin, whereas bacteria pre-incubated in human serum survived exposure to the antibiotic, with >99% cells remaining viable. Incubation of enterococci or streptococci in serum led to peptidoglycan accumulation, as shown by increased incorporation of the fluorescent D-amino analogue HADA. Inhibition of peptidoglycan accumulation using the antibiotic fosfomycin resulted in a >10-fold reduction in serum-induced daptomycin tolerance, demonstrating the important contribution of the cell wall to the phenotype. We also identified a small contribution to daptomycin tolerance in<jats:italic>E. faecalis</jats:italic>from cardiolipin synthases, although this may reflect the inherent susceptibility of cardiolipin-deficient mutants. In summary, serum-induced daptomycin tolerance is a consistent phenomenon between Gram-positive infective endocarditis pathogens, but it may be mitigated using currently available antibiotic combination therapy.</jats:p>
AU  - Tickle,ARH
AU  - Ledger,EVK
AU  - Edwards,AM
DO  - 10.1101/2022.10.12.511873
PY  - 2022///
TI  - Human serum induces daptomycin tolerance in<i>Enterococcus faecalis</i>and viridans group streptococci
UR  - http://dx.doi.org/10.1101/2022.10.12.511873
ER  - 

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