First identification of boronic species as novel potential inhibitors of the Staphylococcus aureus NorA efflux pump.
Overexpression of efflux pumps is an important mechanism of bacterial resistance that results in the extrusion of antimicrobial agents outside the bacterial cell. Inhibition of such pumps appears to be a promising strategy that could restore the potency of existing antibiotics. The NorA efflux pump of Staphylococcus aureus confers resistance to a wide range of unrelated substrates, such as hydrophilic fluoroquinolones, leading to a multidrug-resistance phenotype. In this work, approximately 150 heterocyclic boronic species were evaluated for their activity against susceptible and resistant strains of S. aureus. Twenty-four hit compounds, although inactive when tested alone, were found to potentiate ciprofloxacin activity by a 4-fold increase at concentrations ranging from 0.5 to 8 μg/mL against S. aureus 1199B, which overexpresses NorA. Boron-free analogues showed no biological activity, thus revealing that the boron atom is crucial for biological activity. This work describes the first reported efflux pump inhibitory activity of boronic acid derivatives.
Normandie Univ , France.
Fanny
F
Fontaine
Arnaud
A
Hequet
Anne-Sophie
AS
Voisin-Chiret
Alexandre
A
Bouillon
Aurélien
A
Lesnard
Thierry
T
Cresteil
Claude
C
Jolivalt
Sylvain
S
Rault
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001897:Boronic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002939:Ciprofloxacin / Q000494:pharmacology; D003470:Culture Media; D024881:Drug Resistance, Bacterial; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007202:Indicators and Reagents; D007624:KB Cells; D008826:Microbial Sensitivity Tests; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D001897:Boronic Acids; D002939:Ciprofloxacin; D003470:Culture Media; D007202:Indicators and Reagents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C075040:NorA protein, Staphylococcus