4-Substituted trinems as broad spectrum beta-lactamase inhibitors: structure-based design, synthesis, and biological activity.
A wide variety of pathogens have acquired antimicrobial resistance as an inevitable evolutionary response to the extensive use of antibacterial agents. In particular, one of the most widely used antibiotic structural classes is the beta-lactams, in which the most common and the most efficient mechanism of bacterial resistance is the synthesis of beta-lactamases. Class C beta-lactamase enzymes are primarily cephalosporinases, mostly chromosomally encoded, and are inducible by exposure to some beta-lactam agents and resistant to inhibition by marketed beta-lactamase inhibitors. In an ongoing effort to alleviate this problem a series of novel 4-substituted trinems was designed and synthesized. Significant in vitro inhibitory activity was measured against the bacterial beta-lactamases of class C and additionally against class A. The lead compound LK-157 was shown to be a potent mechanism-based inactivator. Acylation of the active site Ser 64 of the class C enzyme beta-lactamase was observed in the solved crystal structures of two inhibitors complexes to AmpC enzyme from E. cloacae. Structure-activity relationships in the series reveal the importance of the trinem scaffold for inhibitory activity and the interesting potential of the series for further development.
Drug Discovery, Lek Pharmaceuticals d.d., Verovskova 57, SI-1526 Ljubljana, Slovenia.
Ivan
I
Plantan
Lovro
L
Selic
Tomaz
T
Mesar
Petra Stefanic
PS
Anderluh
Marko
M
Oblak
Andrej
A
Prezelj
Lars
L
Hesse
Miha
M
Andrejasic
Mateja
M
Vilar
Dusan
D
Turk
Andrej
A
Kocijan
Tadeja
T
Prevec
Gregor
G
Vilfan
Darko
D
Kocjan
Anton
A
Copar
Uros
U
Urleb
Tom
T
Solmajer
D000215:Acylation; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001384:Azetidines / Q000138:chemical synthesis* / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D016972:Enterobacter cloacae / Q000201:enzymology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry
D000900:Anti-Bacterial Agents; D001384:Azetidines; D001426:Bacterial Proteins; D006575:Heterocyclic Compounds, 3-Ring; D065093:beta-Lactamase Inhibitors; C048795:AmpC beta-lactamases; D001618:beta-Lactamases