Effect of sulbactam on anti-pseudomonal activity of beta-lactam antibiotics in cells producing various levels of the MexAB-OprM efflux pump and beta-lactamase.
The beta-lactamase inhibitor, sulbactam, was tested for beta-lactamase inhibitory activity in Pseudomonas aeruginosa cells producing various levels of both the MexAB-OprM efflux pump and beta-lactamase. We found that sulbactam lowered the MICs of cefoperazone and piperacillin by inhibiting the beta-lactamase 8-fold in the cell producing a constitutively high level of AmpC-type beta-lactamase and a wild-type level of MexAB-OprM pump compared with that without sulbactam. The MICs of cefoperazone and piperacillin in the cell producing a constitutively high level of both the efflux pump and beta-lactamase under the presence of sulbactam were 8 and 4 times, respectively, lower than that without sulbactam. The MICs of sulbactam in the cell producing a constitutively high and a wild-type level of the efflux pump were 16- and 8-fold higher, respectively, than that in the mutant lacking the efflux pump. We concluded that sulbactam exerts potent beta-lactamase inhibitory activity in the cell producing a high level of efflux pump, in spite of the fact that sulbactam serves as a substrate of the MexAB-OprM pump. Increasing amounts of sulbactam over the weight of beta-lactams further strengthen the effect of beta-lactam antibiotics.
Nakae
T
T
Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan. nakae@is.icc.u-tokai.ac.jp
Saito
K
K
Nakajima
A
A
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002438:Cefoperazone / Q000494:pharmacology; D002441:Cefsulodin / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D026901:Membrane Transport Proteins; D008826:Microbial Sensitivity Tests; D010878:Piperacillin / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000378:metabolism; D013407:Sulbactam / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors
D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; C402263:OprM protein, Pseudomonas aeruginosa; D065093:beta-Lactamase Inhibitors; D002438:Cefoperazone; D002441:Cefsulodin; D013407:Sulbactam; D010878:Piperacillin