Mechanism of enhanced antipseudomonal activity of BO-2727, a new injectable 1-beta-methyl carbapenem.
The mechanism of the enhanced activity of BO-2727 against imipenem-resistant Pseudomonas aeruginosa was studied by using a set of four isogenic strains derived from beta-lactamase-deficient P. aeruginosa PAO4089 (blaJ blaP). Complementation of the blaJ and blaP mutations conferred greater resistance to biapenem, panipenem, and imipenem than to BO-2727 and meropenem, most notably in the outer membrane protein D2-deficient strain. The higher levels of resistance to biapenem, panipenem, and imipenem can be explained by the slow but significant hydrolysis by beta-lactamase, whereas the reduced levels of resistance to BO-2727 and meropenem would be attributable to their stability in the presence of high levels of beta-lactamase and the fact that they cause only low induction of beta-lactamase. It is also noted that the activity of BO-2727 against the beta-lactamase-deficient strain was less affected by the loss of the D2 porin than was that of meropenem, indicating that BO-2727 in comparison with meropenem can overcome an intrinsic resistance caused by the loss of D2. Moreover, comparative in vitro resistance studies have shown that BO-2727 and meropenem selected fewer resistant cells than other carbapenems. In conclusion, BO-2727 exhibited improved activity against imipenem-resistant P. aeruginosa, probably because of its ability to overcome loss of the D2 porin and beta-lactamase hydrolysis.
Hazumi
N
N
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Japan.
Fuse
A
A
Matsuda
K
K
Hashizume
T
T
Sanada
M
M
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004591:Electrophoresis, Polyacrylamide Gel; D009154:Mutation; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D001618:beta-Lactamases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D015780:Carbapenems; C085890:BO 2727; D001618:beta-Lactamases