TY - JOUR

T1 - Resveratrol enhances the efficacy of aminoglycosides against Staphylococcus aureus

AU - Nøhr-Meldgaard, Katrine

AU - Ovsepian, Armen

AU - Ingmer, Hanne

AU - Vestergaard, Martin

PY - 2018/9

Y1 - 2018/9

N2 - Development of new antibiotics is costly and time-consuming, and therefore increasing the efficacy of conventional antibiotics is extremely attractive. For the human pathogen, Staphylococcus aureus, inactivation of the ATP synthase increases its susceptibility to gentamicin (an aminoglycoside) 16-fold. Aminoglycosides are rarely used as monotherapy against S. aureus due to the risk of development of resistance and toxic effects. This study explored the possibility of enhancing the efficacy of aminoglycosides against S. aureus and other Gram-positive pathogens by inhibiting the ATP synthase with resveratrol, a polyphenolic ATP synthase inhibitor that is commonly used as a dietary supplement. Co-administration of subinhibitory concentrations of resveratrol increased the activity of aminoglycosides, including gentamicin, kanamycin, neomycin, streptomycin and tobramycin, up to 32-fold against S. aureus, while the effect was lower (2–4-fold reduction in minimum inhibitory concentration) for other Gram-positive pathogens (i.e. Staphylococcus epidermidis, Enterococcus faecium and Enterococcus faecalis). The mechanism by which resveratrol increases the efficacy of aminoglycosides appears to be unrelated to membrane hyperpolarization and disruption of membrane integrity, which have been associated previously with increased aminoglycoside susceptibility. These results demonstrate that inhibition of the ATP synthase increases the efficacy of aminoglycosides against important Gram-positive pathogens, and the ATP synthase should be explored further as a target that may extend the clinical applicability of aminoglycosides.

AB - Development of new antibiotics is costly and time-consuming, and therefore increasing the efficacy of conventional antibiotics is extremely attractive. For the human pathogen, Staphylococcus aureus, inactivation of the ATP synthase increases its susceptibility to gentamicin (an aminoglycoside) 16-fold. Aminoglycosides are rarely used as monotherapy against S. aureus due to the risk of development of resistance and toxic effects. This study explored the possibility of enhancing the efficacy of aminoglycosides against S. aureus and other Gram-positive pathogens by inhibiting the ATP synthase with resveratrol, a polyphenolic ATP synthase inhibitor that is commonly used as a dietary supplement. Co-administration of subinhibitory concentrations of resveratrol increased the activity of aminoglycosides, including gentamicin, kanamycin, neomycin, streptomycin and tobramycin, up to 32-fold against S. aureus, while the effect was lower (2–4-fold reduction in minimum inhibitory concentration) for other Gram-positive pathogens (i.e. Staphylococcus epidermidis, Enterococcus faecium and Enterococcus faecalis). The mechanism by which resveratrol increases the efficacy of aminoglycosides appears to be unrelated to membrane hyperpolarization and disruption of membrane integrity, which have been associated previously with increased aminoglycoside susceptibility. These results demonstrate that inhibition of the ATP synthase increases the efficacy of aminoglycosides against important Gram-positive pathogens, and the ATP synthase should be explored further as a target that may extend the clinical applicability of aminoglycosides.

KW - Aminoglycosides

KW - ATP synthase

KW - Intrinsic resistance

KW - Resveratrol

KW - Staphylococcus aureus

U2 - 10.1016/j.ijantimicag.2018.06.005

DO - 10.1016/j.ijantimicag.2018.06.005

M3 - Journal article

C2 - 29906565

AN - SCOPUS:85050676535

VL - 52

SP - 390

EP - 396

JO - International Journal of Antimicrobial Agents

JF - International Journal of Antimicrobial Agents

SN - 0924-8579

IS - 3

ER -