An alkylaminoquinazoline restores antibiotic activity in Gram-negative resistant isolates.
To date, various bacterial drug efflux pump inhibitors (EPIs) have been described. They exhibit variability in their activity spectrum with respect to antibiotic structural class and bacterial species. Among the various 4-alkylaminoquinazoline derivatives synthesized and studied in this work, one molecule, 1167, increased the susceptibility of important human-pathogenic, resistant, Gram-negative bacteria towards different antibiotic classes. This 4-(3-morpholinopropylamino)-quinazoline induced an increase in the activity of chloramphenicol, nalidixic acid, norfloxacin and sparfloxacin, which are substrates of the AcrAB-TolC and MexAB-OprM efflux pumps that act in these multidrug-resistant isolates. In addition, 1167 increased the intracellular concentration of chloramphenicol in efflux pump-overproducing strains. The rate of restoration depended on the structure of the antibiotic, suggesting that different sites in the efflux pumps may be involved. A molecule exhibiting a morpholine functional group and a propyl extension of the side chain was more active.
UMR-MD-1, Facultés de Médecine et de Pharmacie, Université de la Méditerranée, Marseille, France.
Abdallah
A
Mahamoud
UMR-MD-1, Facultés de Médecine et de Pharmacie, Université de la Méditerranée, Marseille, France.
Jacqueline
J
Chevalier
UMR-MD-1, Facultés de Médecine et de Pharmacie, Université de la Méditerranée, Marseille, France.
Milad
M
Baitiche
UMR-MD-1, Facultés de Médecine et de Pharmacie, Université de la Méditerranée, Marseille, France.
Elissavet
E
Adam
UMR-MD-1, Facultés de Médecine et de Pharmacie, Université de la Méditerranée, Marseille, France.
Jean-Marie
JM
Pagès
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D002701:Chloramphenicol / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D024841:Fluoroquinolones / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009268:Nalidixic Acid / Q000494:pharmacology; D009643:Norfloxacin / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D024841:Fluoroquinolones; D026901:Membrane Transport Proteins; D011799:Quinazolines; D009268:Nalidixic Acid; D002701:Chloramphenicol; D009643:Norfloxacin; C061363:sparfloxacin