title: Boronic species as promising inhibitors of the Staphylococcus aureus NorA efflux pump: study of 6-substituted pyridine-3-boronic acid derivatives.
abstract: In response to the extensive use of antibiotics, bacteria have evolved numerous mechanisms of defense against antimicrobial agents. Among them, extrusion of the antimicrobial agents outside the bacterial cell through efflux pumps is a major cause of concern. At first limited to one or few structurally-related antibiotics, bacterial resistance have then progressed towards cross-resistance between different classes of antibiotics, leading to multidrug-resistant microorganisms. Emergence of these pathogens requires development of novel therapeutic strategies and inhibition of efflux pumps appears to be a promising strategy that could restore the potency of existing antibiotics. NorA is the most studied chromosomal efflux pump of Staphylococcus aureus; it is known to be implied in resistance of Methicillin-resistant S. aureus (MRSA) strains against a wide range of unrelated substrates, including hydrophilic fluoroquinolones. Starting from 6-benzyloxypyridine-3-boronic acid I that we previously identified as a potential inhibitor of the NorA efflux pump against the NorA-overexpressing S. aureus 1199B strain (SA1199B), we describe here the synthesis and biological evaluation of a series of 6-(aryl)alkoxypyridine-3-boronic acids. 6-(3-Phenylpropoxy)pyridine-3-boronic acid 3i and 6-(4-phenylbutoxy)pyridine-3-boronic acid 3j were found to potentiate ciprofloxacin activity by a 4-fold increase compared to the parent compound I. In addition, it has been shown that both compounds promote Ethidium Bromide (EtBr) accumulation in SA1199B, thus corroborating their potential mode of action as NorA inhibitors.
authors.affiliation: Normandie Univ, France; UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie) - FR CNRS INC3M, Boulevard Becquerel, 14032 Caen, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Fontaine
authors.affiliation: Chimie ParisTech (Ecole Nationale Supérieure de Chimie de Paris), Laboratoire Charles Friedel, UMR-7223, CNRS, 11 Rue Pierre et Marie Curie, F-75231 Paris Cedex 05, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Héquet
authors.affiliation: Normandie Univ, France; UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie) - FR CNRS INC3M, Boulevard Becquerel, 14032 Caen, France. Electronic address: anne-sophie.voisin@unicaen.fr.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Voisin-Chiret
authors.affiliation: BoroChem S.A.S., 10 Rue du Professeur Zarifian, F-14200 Hérouville Saint Clair, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bouillon
authors.affiliation: Normandie Univ, France; UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie) - FR CNRS INC3M, Boulevard Becquerel, 14032 Caen, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Lesnard
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS, UPR 2301, Avenue de la Terrasse, F-91198 Gif sur Yvette, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Cresteil
authors.affiliation: Chimie ParisTech (Ecole Nationale Supérieure de Chimie de Paris), Laboratoire Charles Friedel, UMR-7223, CNRS, 11 Rue Pierre et Marie Curie, F-75231 Paris Cedex 05, France; Sorbonne Universités, UPMC Univ Paris 06, CNRS UMR 7197 Laboratoire de Réactivité de Surface, F-75005 Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Jolivalt
authors.affiliation: Normandie Univ, France; UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie) - FR CNRS INC3M, Boulevard Becquerel, 14032 Caen, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000494:pharmacology; D006801:Humans; D007624:KB Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001897:Boronic Acids; D002939:Ciprofloxacin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011725:Pyridines; C000604758:6-(3-Phenylpropoxy)pyridine-3-boronic acid; C075040:NorA protein, Staphylococcus
keywords: Antimicrobial agents; Boronic acids; Efflux pump inhibitors; Pyridine derivatives; Staphylococcus aureus