New pyridoquinoline derivatives as potential inhibitors of the fluoroquinolone efflux pump in resistant Enterobacter aerogenes strains.
Enterobacter aerogenes, one of the most frequently isolated nosocomial pathogens in France, is exhibiting increasing multidrug resistance mechanisms associated with a change in membrane permeability. For drugs of the quinolone family, mutations in the target and active efflux play a prominent role in the resistance. We report here the effect of several pyridoquinoline derivatives that restore a noticeable fluoroquinolone accumulation to resistant strains that overexpress the MarA activator. Studies of the energy-dependent quinolone efflux indicate that the most efficient derivatives tested probably inhibit the resistance process by acting as substrate competitors on the pump extruding intracellular norfloxacin.
Chevalier
J
J
CJF9606-EA2197, Faculté de Médecine, Université de la Méditerranée, 13385 Marseille, Cedex 05, France.
Atifi
S
S
Eyraud
A
A
Mahamoud
A
A
Barbe
J
J
Pagès
J M
JM
D000890:Anti-Infective Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004336:Drug Antagonism; D024881:Drug Resistance, Bacterial; D018432:Drug Resistance, Multiple; D021902:Enterobacter aerogenes / Q000187:drug effects* / Q000378:metabolism; D029968:Escherichia coli Proteins; D008826:Microbial Sensitivity Tests; D009643:Norfloxacin / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; C080002:MarA protein, E coli; D011804:Quinolines; D009643:Norfloxacin