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Antimicrobial Agents and Chemotherapy, February 2009, p. 505-511, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00085-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

In Vitro Activity of LK-157, a Novel Tricyclic Carbapenem As Broad-Spectrum β-Lactamase Inhibitor{triangledown}

Susanne Paukner,1 Lars Hesse,1 Andrej Prezelj,2* Tomaz Solmajer,3 and Uros Urleb2

Nabriva Therapeutics AG, Vienna, Austria,1 Lek Pharmaceuticals, d.d., Drug Discovery, Ljubljana, Slovenia,2 National Institute of Chemistry, Ljubljana, Slovenia3

Received 21 January 2008/ Returned for modification 30 March 2008/ Accepted 27 November 2008

LK-157 is a novel tricyclic carbapenem with potent activity against class A and class C β-lactamases. When tested against the purified TEM-1 and SHV-1 enzymes, LK-157 exhibited 50% inhibitory concentrations (IC50s) in the ranges of the clavulanic acid and tazobactam IC50s (55 nM and 151 nM, respectively). Moreover, LK-157 significantly inhibited AmpC β-lactamase (IC50, 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 (≤0.025 to 1.6 µg/ml) were observed for the combination of cefepime and cefpirome with a constant LK-157 concentration of 4 µg/ml, thus raising an interest for further development. LK-157 proved to be a potent β-lactamase inhibitor, combining activity against class A and class C β-lactamases, which is an absolute necessity for use in the clinical setting due to the worldwide increasing prevalence of bacterial strains resistant to β-lactam antibiotics.

* Corresponding author. Mailing address: Lek Pharmaceuticals, d.d., Drug Discovery, Verovskova 57, SI-1526 Ljubljana, Slovenia. Phone: 386 1/580 35 44. Fax: 386 1/568 23 40. E-mail: andrej.prezelj{at}sandoz.com

{triangledown} Published ahead of print on 15 December 2008.

Antimicrobial Agents and Chemotherapy, February 2009, p. 505-511, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00085-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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