ABSTRACT
Enterobacter aerogenes is a Gram-negative bacteria frequently responsible for nosocomial respiratory tract infections. Strains resistant to chloramphenicol are frequently isolated. Alkoxy and thio-alkoxyquinolines have a potential to act as chemosensitizers that would render multi-drug-resistant (MDR) bacterial infections susceptible to antibiotics to which they were originally resistant. Several new quinoline derivatives have been prepared, characterized and studied for their ability to increase chloramphenicol sensitivity of E. aerogenes 27, a clinical strain that exhibits the MDR phenotype. Drugs investigated were either quinoline ethers or quinoline thio-ethers. Thio-ethers are much more efficient in increasing chloramphenicol sensitivity than other corresponding ethers. In particular, 4-piperidinoethylthio-quinoline increases the strain sensitivity to chloramphenicol by about 20 times at 2 mM concentration. Similarly, sensitivity to quinolone antibiotics dramatically increases. Because these quinoline derivatives act as inhibitors of the drug efflux pump responsible for bacterial resistance to chloramphenicol, they may serve as adjunct to conventional therapy of E. aerogenes infections.
Subject(s)
Chloramphenicol/pharmacology , Enterobacter aerogenes/drug effects , Quinolines/pharmacology , Anti-Bacterial Agents/metabolism , Biological Transport, Active/drug effects , Cross Infection/drug therapy , Cross Infection/microbiology , Drug Interactions , Drug Resistance, Multiple, Bacterial , Enterobacter aerogenes/isolation & purification , Enterobacter aerogenes/metabolism , Enterobacteriaceae Infections/drug therapy , Enterobacteriaceae Infections/microbiology , Humans , In Vitro Techniques , Quinolines/chemistry , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/microbiologyABSTRACT
Enterobacter aerogenes, a nosocomial pathogen, is frequently exhibiting multidrug resistance mechanisms associated with a change in membrane permeability. In clinical isolates, active efflux plays a prominent role in antibiotic resistance. We report here the effect of three unrelated compounds that are able to restore a noticeable antibiotic susceptibility to resistant strains. The targeting of various parameters which contribute to the efficacy of the efflux mechanism, such as energy, flux selectivity, or functional assembly of the membrane complex, increases the intracellular chloramphenicol concentration in resistant isolates.
Subject(s)
Anti-Bacterial Agents/pharmacology , Enterobacter aerogenes/metabolism , Peptides , Anti-Bacterial Agents/chemistry , Chloramphenicol/metabolism , Chloramphenicol/pharmacokinetics , Enterobacter aerogenes/chemistry , Time FactorsABSTRACT
Enterobacter aerogenes is among the five most frequently isolated nosocomial pathogens in France, and this bacterium also shows increasing multidrug resistance. In this study, various E. aerogenes strains isolated from hospital units were characterized for their outer-membrane proteins, antibiotic susceptibilities (inhibition diameters and MICs) and resistance mechanisms associated with modification of envelope permeability (porin alteration and active efflux). Diminished outer-membrane permeability due to porin alterations was found in conjunction with the expression of an enzymic barrier in resistant isolates. Interestingly, changes in the functional expression of porins appeared to play a special role in susceptibility to cefepime. An active efflux to quinolones was also identified. Simultaneous changes in envelope permeability, i.e. a porin deficiency (in) and an efflux mechanism (out), were clearly evident in two clinical strains.
