Membrane permeability and regulation of drug "influx and efflux" in enterobacterial pathogens.
In Enterobacteriaceae, membrane permeability is a key in the level of susceptibility to antibiotics. Modification of the bacterial envelope by decreasing the porin production or increasing the expression of efflux pump systems has been reported. These phenomena are frequently associated with other resistance mechanisms such as alteration of antibiotics or modification of the drug targets, in various clinical isolates showing a Multi Drug Resistant phenotype (MDR). In Escherichia coli, Enterobacter aerogenes, Klebsiella pneumoniae and Salmonella enterica several genes and external factors are involved in the emergence of MDR isolates. These bacterial isolates exhibit a noticeable reduction of functional porins per cell due to a decrease, a complete shutdown of synthesis, or the expression of an altered porin and a high expression of efflux systems (e.g. overexpression of the pump). The combined action of these mechanisms during an infection confers a significant decrease in bacterial sensitivity to antibiotherapy ensuring dissemination and colonization of the patient and favours the acquisition of additional mechanisms of resistance. MarA and ramA are involved in a complex regulation cascade controlling membrane permeability and actively participate in the triggering of the MDR phenotype. Mutations in regulator genes have been shown to induce the overproduction of efflux and the down-regulation of porin synthesis. In addition, various compounds such as salicylate, imipenem or chloramphenicol are able to activate the MDR response. This phenomenon has been observed both in vitro during culture of bacteria in the presence of drugs and in vivo during antibiotic treatment of infected patients. These effectors activate the expression of specific global regulators, marA, ramA, or target other genes located downstream in the regulation cascade.
Davin-Regli
Anne
A
UMR-MD-1, Transporteurs Membranaires, Chimioresistance et Drug-Design, Facultés de Médecine et de Pharmacie, Université de la Méditerranée, Marseille, France.
Bolla
Jean-Michel
JM
James
Chloë E
CE
Lavigne
Jean-Philippe
JP
Chevalier
Jacqueline
J
Garnotel
Eric
E
Molitor
Alexander
A
Pagès
Jean-Marie
JM
D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001692:Biological Transport / Q000235:genetics; D002463:Cell Membrane Permeability / Q000502:physiology*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects / Q000235:genetics; D004755:Enterobacteriaceae / Q000235:genetics / Q000378:metabolism*; D004756:Enterobacteriaceae Infections / Q000188:drug therapy; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D018272:Porins / Q000096:biosynthesis
D000900:Anti-Bacterial Agents; D018272:Porins