title: 4-quinolones as noncovalent inhibitors of high molecular mass penicillin-binding proteins.
abstract: Penicillin-binding proteins (PBPs) are important bacterial enzymes that carry out the final steps of bacterial cell wall assembly. Their DD-transpeptidase activity accomplishes the essential peptide cross-linking step of the cell wall. To date, all attempts to discover effective inhibitors of PBPs, apart from β-lactams, have not led to new antibiotics. Therefore, the need for new classes of efficient inhibitors of these enzymes remains. Guided by a computational fragment-based docking procedure, carried out on Escherichia coli PBP5, we have designed and synthesized a series of 4-quinolones as potential inhibitors of PBPs. We describe their binding to the PBPs of E. coli and Bacillus subtilis. Notably, these compounds bind quite tightly to the essential high molecular mass PBPs.
authors.affiliation: Department of Chemistry, Wesleyan University , Middletown, Connecticut 06459, United States.
authors.forename: Abbas G
authors.initials: AG
authors.lastname: Shilabin
authors.affiliation: Department of Chemistry, Wesleyan University , Middletown, Connecticut 06459, United States.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Dzhekieva
authors.affiliation: Department of Chemistry, IIT Delhi , Hauz Khas, New Delhi 110016, India.
authors.forename: Pushpa
authors.initials: P
authors.lastname: Misra
authors.affiliation: Department of Chemistry, IIT Delhi , Hauz Khas, New Delhi 110016, India.
authors.forename: B
authors.initials: B
authors.lastname: Jayaram
authors.affiliation: Department of Chemistry, Wesleyan University , Middletown, Connecticut 06459, United States.
authors.forename: R F
authors.initials: RF
authors.lastname: Pratt
keywords: 4-quinolone; DD-peptidase; Penicillin-binding protein; noncovalent inhibitor