Abstract
Treatment of Staphylococcus aureus in stationary growth phase with high doses of the antibiotic daptomycin (DAP) eradicates the vast majority of the culture and leaves persister cells behind. Despite resting in a drug-tolerant and dormant state, persister cells exhibit metabolic activity which might be exploited for their elimination. We here report that the addition of glucose to S. aureus persisters treated with DAP increased killing by up to five-fold within one hour. This glucose-DAP effect also occurred with strains less sensitive to the drug. The underlying mechanism is independent of the proton motive force and was not observed with non-metabolizable 2-deoxy-glucose. Our results are consistent with two hypotheses on the glucose-DAP interplay. The first is based upon glucose-induced carbohydrate transport proteins that may influence DAP and the second suggests that glucose may trigger the release or activity of cell-lytic proteins to augment DAP’s mode of action.
Highlights
Eradication of harmful bacteria in the human body is often cumbersome due to drug resistance and drug tolerance in biofilm embedded cells [1,2,3,4,5,6,7]
Three SA113 cultures were grown identically in TSB medium to stationary growth phase at which the medium is depleted for glucose [23]. 100-fold the MIC of DAP was added at time point t = 0h to each of the cultures and at t = 3h, 5h or 7h, respectively, one culture each was supplemented with glucose at a final concentration of 5 g/L The viable counts indicated significantly enhanced killing when glucose was added at t = 3h compared to a culture challenged with DAP only (Fig 1)
We have previously shown that stationary growth phase S. aureus cultures are extremely tolerant to a number of antibiotics in vitro, even at elevated drugconcentrations [35]
Summary
Eradication of harmful bacteria in the human body is often cumbersome due to drug resistance and drug tolerance in biofilm embedded cells [1,2,3,4,5,6,7]. Biofilms accommodate a high percentage of persister cells which are in a non-dividing and metabolically less active state [8]. Persisters are regarded as genetically identical variants among a population of unicellular organisms that tolerate and survive high concentrations of antibiotics over extended periods of time [9,10,11,12]. This kind of phenotypic heterogeneity is a successful bet-hedging strategy to endure hostile conditions, such as antibiotic treatment or immune response and provides a rationale for recurrent or chronic bacterial infections [9,13,14]. Compared to the identification of numerous persister-genes, information available on metabolic aspects of persisters is more limited
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