STRUCTURE-ACTIVITY-RELATIONSHIPS OF CARBAPENEMS THAT DETERMINE THEIR DEPENDENCE ON PORIN PROTEIN D2 FOR ACTIVITY AGAINST PSEUDOMONAS-AERUGINOSA

A number of carbapenem derivatives were examined to determine the stru cture-activity relationships required for dependence on porin protein D2 for activity against Pseudomonas aeurginosa. As suggested by J. (An timicrob. Agents Chemother. 34:52-57, 1990), carbapenem derivatives, s uch as imipenem and meropenem, containing a sole basic group at positi on 2 of the molecule utilize the D2 channel for permeation through the outer membrane of pseudomonads; they are more active against D2-suffi cient strains of P. aeruginosa. Our results indicated that carbapenems with a basic group at position 1 or 6 of the molecule did not depend on the D2 channel for activity; i.e., they were equally active against DZ-sufficient and D2-deficient pseudomonal strains. However, addition of a basic group at position 1 or 6 of a carbapenem derivative alread y containing a basic group at position 2 resulted in its lack of depen dency on the D2 pathway. Comparison between meropenem and its 1-guanid inoethyl derivative, BMY 45047, indicated that they differed in their dependence on D2; while meropenem required the D2 channel for uptake. BMY 45047 activity was independent of D2. Meropenem and BMY 45047 had similar affinities for the penicillin-binding proteins of P., aerugino sa. However, BMY 45047 and meropenem differed in the morphological cha nges that they induced in pseudomonal cells, While meropenem induced f ilamentation, BMY 45047 induced filaments only in BMS-181139-resistant mutants and not in imipenem-resistant mutants or in carbapenem-suscep tible P. aeruginosa strains. These results suggested that in Mueller-H inton medium the uptake of BMY 45047 through the non-D2 pathway is mor e rapid than that of meropenem through the D2 porin. In summary, the p resence of a basic group at position 2 of a carbapenem is important fo r its preferential uptake by the D2 channel. However, the addition of a basic group at position 1 or 6 of a carbapenem already containing a basic group at position 2 dissociates its necessity for porin protein D2 for activity.