Quinazoline derivatives are efficient chemosensitizers of antibiotic activity in Enterobacter aerogenes, Klebsiella pneumoniae and Pseudomonas aeruginosa resistant strains.
Amongst the three series of quinazoline derivatives synthesised and studied in this work, some molecules increase the antibiotic susceptibility of Gram-negative bacteria presenting multidrug-resistant phenotypes. N-alkyl compounds induced an increase in the activity of chloramphenicol, nalidixic acid and sparfloxacin, which are substrates of the AcrAB-TolC and MexAB-OprM efflux pumps in clinical isolates. These molecules are able to increase the intracellular concentration of chloramphenicol in efflux pump-overproducing strains. Their activity depends on the antibiotic structure, suggesting that different sites may be involved for the recognition of substrates by a given efflux pump. Quinazoline molecules exhibiting a nitro functional group are more active, and structure-activity relationship studies may be undertaken to identify the pharmacophoric group involved in the AcrB and MexB affinity sites.
Chevalier
Jacqueline
J
UMR-MD1, Facultés de Médecine et de Pharmacie, Université de la Méditerranée, IFR88, Marseille, France.
Mahamoud
Abdallah
A
Baitiche
Milad
M
Adam
Elissavet
E
Viveiros
Miguel
M
Smarandache
Adriana
A
Militaru
Andra
A
Pascu
Mihail L
ML
Amaral
Leonard
L
Pagès
Jean-Marie
JM
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002701:Chloramphenicol / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D021902:Enterobacter aerogenes / Q000187:drug effects*; D024841:Fluoroquinolones / Q000494:pharmacology; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D009268:Nalidixic Acid / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D011799:Quinazolines; D009268:Nalidixic Acid; D002701:Chloramphenicol; C061363:sparfloxacin