title: Inhibition of DD-peptidases by a specific trifluoroketone: crystal structure of a complex with the Actinomadura R39 DD-peptidase.
abstract: Inhibitors of bacterial DD-peptidases represent potential antibiotics. In the search for alternatives to β-lactams, we have investigated a series of compounds designed to generate transition state analogue structures upon reaction with DD-peptidases. The compounds contain a combination of a peptidoglycan-mimetic specificity handle and a warhead capable of delivering a tetrahedral anion to the enzyme active site. The latter includes a boronic acid, two alcohols, an aldehyde, and a trifluoroketone. The compounds were tested against two low-molecular mass class C DD-peptidases. As expected from previous observations, the boronic acid was a potent inhibitor, but rather unexpectedly from precedent, the trifluoroketone [D-α-aminopimelyl(1,1,1-trifluoro-3-amino)butan-2-one] was also very effective. Taking into account competing hydration, we found the trifluoroketone was the strongest inhibitor of the Actinomadura R39 DD-peptidase, with a subnanomolar (free ketone) inhibition constant. A crystal structure of the complex between the trifluoroketone and the R39 enzyme showed that a tetrahedral adduct had indeed formed with the active site serine nucleophile. The trifluoroketone moiety, therefore, should be considered along with boronic acids and phosphonates as a warhead that can be incorporated into new and effective DD-peptidase inhibitors and therefore, perhaps, antibiotics.
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: Raphael
authors.initials: R
authors.lastname: Herman
authors.forename: Frédéric
authors.initials: F
authors.lastname: Kerff
authors.forename: Colette
authors.initials: C
authors.lastname: Duez
authors.forename: Paulette
authors.initials: P
authors.lastname: Charlier
authors.forename: Eric
authors.initials: E
authors.lastname: Sauvage
authors.forename: R F
authors.initials: RF
authors.lastname: Pratt
mesh_terms: D000192:Actinomycetales / Q000201:enzymology*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002074:Butanones / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002074:Butanones; D011480:Protease Inhibitors; D047090:beta-Lactams; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase