Beta-ketophosphonates as beta-lactamase inhibitors: Intramolecular cooperativity between the hydrophobic subsites of a class D beta-lactamase.
A series of aryl and arylmethyl beta-aryl-beta-ketophosphonates have been prepared as potential beta-lactamase inhibitors. These compounds, as fast, reversible, competitive inhibitors, were most effective (micromolar K(i) values) against the class D OXA-1 beta-lactamase but had less activity against the OXA-10 enzyme. They were also quite effective against the class C beta-lactamase of Enterobacter cloacae P99 but less so against the class A TEM-2 enzyme. Reduction of the keto group to form the corresponding beta-hydroxyphosphonates led to reduced inhibitory activity. Molecular modeling, based on the OXA-1 crystal structure, suggested interaction of the aryl groups with the hydrophobic elements of the enzyme's active site and polar interaction of the keto and phosphonate groups with the active site residues Ser 115, Lys 212 and Thr 213 and with the non-conserved Ser 258. Analysis of binding free energies showed that the beta-aryl and phosphonate ester aryl groups interacted cooperatively within the OXA-1 active site. Overall, the results suggest that quite effective inhibitors of class C and some class D beta-lactamases could be designed, based on the beta-ketophosphonate platform.
Department of Chemistry, Wesleyan University, Middletown, CT 06459, USA.
Senthil K
SK
Perumal
S A
SA
Adediran
R F
RF
Pratt
D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001665:Binding Sites; D001667:Binding, Competitive; D016972:Enterobacter cloacae / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D007659:Ketones; D008958:Models, Molecular; D063065:Organophosphonates / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007659:Ketones; D063065:Organophosphonates; D065093:beta-Lactamase Inhibitors; C039404:beta-lactamase OXA-2; D001618:beta-Lactamases; C056342:beta-lactamase TEM-2