In vitro activity of LK-157, a novel tricyclic carbapenem as broad-spectrum {beta}-lactamase inhibitor

• Published in: Antimicrobial agents and chemotherapy Vol. 53; no. 2; pp. 505 - 511
• Main Authors: Paukner, Susanne, Hesse, Lars, Prezelj, Andrej, Solmajer, Tomaz, Urleb, Uros
• Format: Journal Article
• Language: English
• Published: United States 01.02.2009
• Subjects: Anti-Bacterial Agents - pharmacology; Bacteria - drug effects; Bacterial Proteins - antagonists & inhibitors; beta-Lactamase Inhibitors; beta-Lactamases; Carbapenems - pharmacology; Drug Resistance, Bacterial - drug effects; Enzyme Inhibitors - pharmacology; Microbial Sensitivity Tests
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00085-08

LK-157 is a novel tricyclic carbapenem with potent activity against class A and class C beta-lactamases. When tested against the purified TEM-1 and SHV-1 enzymes, LK-157 exhibited 50% inhibitory concentrations (IC(50)s) in the ranges of the clavulanic acid and tazobactam IC(50)s (55 nM and 151 nM, respectively). Moreover, LK-157 significantly inhibited AmpC beta-lactamase (IC(50), 62 nM), as LK-157 was >2,000-fold more potent than clavulanic acid and approximately 28-fold more active than tazobactam. The in vitro activities of LK-157 in combination with amoxicillin, piperacillin, ceftazidime, cefotaxime, ceftriaxone, cefepime, cefpirome, and aztreonam against an array of Ambler class A (TEM-, SHV-, CTX-M-, KPC-, PER-, BRO-, and PC-type)- and class C-producing bacterial strains derived from clinical settings were evaluated in synergism experiments and compared with those of clavulanic acid, tazobactam, and sulbactam. In vitro MICs against ESBL-producing strains (except CTX-M-containing strains) were reduced 2- to >256-fold, and those against AmpC-producing strains were reduced even up to >32-fold. The lowest MICs (< or =0.025 to 1.6 microg/ml) were observed for the combination of cefepime and cefpirome with a constant LK-157 concentration of 4 microg/ml, thus raising an interest for further development. LK-157 proved to be a potent beta-lactamase inhibitor, combining activity against class A and class C beta-lactamases, which is an absolute necessity for use in the clinical setting due to the worldwide increasing prevalence of bacterial strains resistant to beta-lactam antibiotics.