title: The mode of action of 2-(thiazol-2-ylthio)-1beta-methylcarbapenems against Pseudomonas aeruginosa: the impact of outer membrane permeability and the contribution of MexAB-OprM efflux system.
abstract: The mode of action of a series of 2-(4-dihydropyrrolylthiazol-2-ylthio) and 2-(4-tetrahydropyridinylthiazol-2-ylthio)-1beta-methylcarbapenem analogues against Pseudomonas aeruginosa was investigated with regard to contributions of the affinity for penicillin binding proteins (PBPs), the outer membrane permeability, and the effect of the MexAB-OprM efflux system. In this series of carbapenems, the introduction of a substituent in C-2 side chain with a change in physicochemical properties affected the antipseudomonal activity depending on the molecular weight. However, these structural modifications did not affect the affinity for pseudomonal PBPs significantly. It was confirmed that the affinity for PBPs was not an important determinant of the antipseudomonal activity of this series of carbapenems. OprD porin-deficiency did not affect antipseudomonal activity either. On the other hand, the MIC of these carbapenems against P. aeruginosa significantly decreased in the presence of outer membrane permeabilizer. This result strongly suggests that the cause of the relatively low antipseudomonal activity of these carbapanems is their low permeability through the outer membrane of P. aeruginosa. And also, in the presence of outer membrane permeabilizer, the MICs against MexAB-OprM deficient mutants remarkably decreased and were very close to the value of the IC(50) for pseudomonal PBPs. From this result, it was clear that the effect of the MexAB-OprM efflux system was also an important determinant of antipseudomonal activity of these carbapenems. In conclusion, the major determinants of the antipseudomonal activity of the 2-(thiazol-2-ylthio)-1beta-methylcarbapenems are the outer membrane permeability and the effect of the MexAB-OprM efflux system, not the affinity for pseudomonal PBPs.
authors.affiliation: Dainippon Sumitomo Pharma Co., Ltd., Pharmacology Research Laboratories, Kasugade Naka, Osaka, Japan. ken-eguchi@ds-pharma.co.jp
authors.forename: Ken
authors.initials: K
authors.lastname: Eguchi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ueda
authors.forename: Katsunori
authors.initials: K
authors.lastname: Kanazawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Sunagawa
authors.forename: Naomasa
authors.initials: N
authors.lastname: Gotoh
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015780:Carbapenems / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008566:Membranes / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D046915:Penicillin-Binding Proteins / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D015780:Carbapenems; D026901:Membrane Transport Proteins; C402263:OprM protein, Pseudomonas aeruginosa; D046915:Penicillin-Binding Proteins; D013844:Thiazoles