title: Interactions of "bora-penicilloates" with serine β-lactamases and DD-peptidases.
abstract: Specific boronic acids are generally powerful tetrahedral intermediate/transition state analogue inhibitors of serine amidohydrolases. This group of enzymes includes bacterial β-lactamases and DD-peptidases where there has been considerable development of boronic acid inhibitors. This paper describes the synthesis, determination of the inhibitory activity, and analysis of the results from two α-(2-thiazolidinyl) boronic acids that are closer analogues of particular tetrahedral intermediates involved in β-lactamase and DD-peptidase catalysis than those previously described. One of them, 2-[1-(dihydroxyboranyl)(2-phenylacetamido)methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid, is a direct analogue of the deacylation tetrahedral intermediates of these enzymes. These compounds are micromolar inhibitors of class C β-lactamases but, very unexpectedly, not inhibitors of class A β-lactamases. We rationalize the latter result on the basis of a new mechanism of boronic acid inhibition of the class A enzymes. A stable inhibitory complex is not accessible because of the instability of an intermediate on its pathway of formation. The new boronic acids also do not inhibit bacterial DD-peptidases (penicillin-binding proteins). This result strongly supports a central feature of a previously proposed mechanism of action of β-lactam antibiotics, where deacylation of β-lactam-derived acyl-enzymes is not possible because of unfavorable steric interactions.
authors.affiliation: Department of Chemistry, Wesleyan University , Lawn Avenue, Middletown, Connecticut 06459, United States.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Dzhekieva
authors.forename: S A
authors.initials: SA
authors.lastname: Adediran
authors.forename: R F
authors.initials: RF
authors.lastname: Pratt
mesh_terms: D000215:Acylation / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D055162:Biocatalysis / Q000187:drug effects; D001897:Boronic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020134:Catalytic Domain; D015195:Drug Design; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001897:Boronic Acids; D007527:Isoenzymes; D008565:Membrane Proteins; D046915:Penicillin-Binding Proteins; D015842:Serine Proteinase Inhibitors; D065093:beta-Lactamase Inhibitors; C008782:penicilloic acid; D012694:Serine; D010397:Penicillanic Acid; D012697:Serine Endopeptidases; D001618:beta-Lactamases