Abstract
BackgroundCranberry fruits possess many biological activities partly due to their various phenolic compounds; however the underlying modes of action are poorly understood. We studied the effect of cranberry fruit extracts on the gene expression of Staphylococcus aureus to identify specific cellular processes involved in the antibacterial action.MethodsTranscriptional profiles of four S. aureus strains grown in broth supplemented or not with 2 mg/ml of a commercial cranberry preparation (Nutricran®90) were compared using DNA arrays to reveal gene modulations serving as markers for biological activity. Ethanol extracted pressed cakes from fresh fruits also produced various fractions and their effects on marker genes were demonstrated by qPCR. Minimal inhibitory concentrations (MICs) of the most effective cranberry fraction (FC111) were determined against multiple S. aureus strains and drug interactions with β-lactam antibiotics were also evaluated. Incorporation assays with [3H]-radiolabeled precursors were performed to evaluate the effect of FC111 on DNA, RNA, peptidoglycan (PG) and protein biosynthesis.ResultsTreatment of S. aureus with Nutricran®90 or FC111 revealed a transcriptional signature typical of PG-acting antibiotics (up-regulation of genes vraR/S, murZ, lytM, pbp2, sgtB, fmt). The effect of FC111 on PG was confirmed by the marked inhibition of incorporation of D-[3H]alanine. The combination of β-lactams and FC111 in checkerboard assays revealed a synergistic activity against S. aureus including strain MRSA COL, which showed a 512-fold drop of amoxicillin MIC in the presence of FC111 at MIC/8. Finally, a therapeutic proof of concept was established in a mouse mastitis model of infection. S. aureus-infected mammary glands were treated with amoxicillin, FC111 or a combination of both; only the combination significantly reduced bacterial counts from infected glands (P<0.05) compared to the untreated mice.ConclusionsThe cranberry fraction FC111 affects PG synthesis of S. aureus and acts in synergy with β-lactam antibiotics. Such a fraction easily obtained from poorly exploited press-cake residues, may find interesting applications in the agri-food sector and help reduce antibiotic usage in animal food production.
Highlights
Cranberry fruits possess many biological activities partly due to their various phenolic compounds; the underlying modes of action are poorly understood
The NC90 and the press cake (PC) fraction FC111 are bactericidal and affect the transcription of genes associated with a cell wall stress The Minimal inhibitory concentrations (MICs) of the cranberry product NC90 against S. aureus ATCC 29213, Newbould and methicillin-resistant S. aureus (MRSA) COL was 2 mg/mL
In an attempt to understand the basis of the growth inhibitory effect of NC90 observed on S. aureus, we studied the modulation of bacterial gene expression for a variety of strains by microarray analyses (Table 1)
Summary
Cranberry fruits possess many biological activities partly due to their various phenolic compounds; the underlying modes of action are poorly understood. Staphylococcus aureus is an opportunistic pathogen responsible for many infectious diseases in humans and animals [1] This bacterium is among the most prevalent causes of food poisoning gastroenteritis worldwide [2], as well as a leading cause of intramammary infections (gland inflammation, mastitis) in cows, milk quality and yield reduction, and major economic losses for the dairy industry [3]. Treating S. aureus infections becomes increasingly challenging due to its capacity to develop enhanced antibiotic resistance Such resistance has developed due to the protective effects provided by biofilm production [6], chromosomal mutations, the acquisition or expression of various antibiotic resistance genes including those encoding low-affinity penicillin-binding proteins (PBPs) involved in cell wall peptidoglycan biosynthesis, and efflux pumps [7,8]
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