Outer membrane permeability and effect of basic amino acids on antipseudomonal activity of carbapenems.
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Carbapenems, such as panipenem and imipenem, showed better therapeutic efficacy against murine systemic infections caused by <I>Pseudomonas aeruginosa</I> than the activity expected from their MICs determined by using Mueller-Hinton medium. The mechanism was investigated and concluded that outer membrane permeability of <I>P. aeruginosa</I> played important role on carbapenem's antipseudomonal activity as well as existence of postantibiotic effect and strong bactericidal activity of carbapenem. Carbapenems showed 8 to 16 times lower MICs in low-nutritional media than those determined in Mueller-Hinton medium. Basic amino acids, such as L-lysine, L-histidine, and L-arginine, were responsible for the decreased antipseudomonal activity of carbapenems in Mueller-Hinton medium. Other amino acids had little effect on antipseudomonal activity. The effect of basic amino acids on antipseudomonal activity of carbapenem was concentration dependent. OprD-deficient mutants were isolated from <I>P. aeruginosa</I> PAO 1 and examined for their susceptibility to carbapenems with or without presence of basic amino acids. It is concluded that the decreased antipseudomonal activity of carbapenems was caused by competing permeation of carbapenems and basic amino acids through OprD channel of <I>P. aeruginosa</I>. Such influence by basic amino.acids was specific for carbapenems and it was not observed for cephems, penicillin, new quinolones, and aminoglycoside. Uptake of <SUP>14</SUP>C-panipenem into <I>P. aeruginosa</I> PAO 1 was almost suppressed by 100mM L-lysine, and the inhibition of <SUP>14</SUP>C-panipenem uptake was not observed in the OprD-deficient mutant. Concentrations of free basic amino acids are much lower in human serum than in Mueller-Hinton medium (less than 1/40). This is probably one main reason for carbapenem's stronger antipseudomonal activity than that expected from their MICs determined in Mueller-Hinton medium.
- 公益社団法人 日本化学療法学会の論文
公益社団法人 日本化学療法学会 | 論文
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