Antimicrobial agents and chemotherapy · 2008
Discovery and characterization of QPT-1, the progenitor of a new class of bacterial topoisomerase inhibitors.
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Miller Alita A, Bundy Gordon L, Mott John E, Skepner Jill E, Boyle Timothy P, Harris Douglas W, Hromockyj Alexander E, Marotti Keith R, Zurenko Gary E, Munzner Jennifer B, Sweeney Michael T, Bammert Gary F, Hamel Judith C, Ford Charles W, Zhong Wei-Zhu, Graber David R, Martin Gary E, Han Fusen, Dolak Lester A, Seest Eric P, Ruble J Craig, Kamilar Gregg M, Palmer John R, Banitt Lee S, Hurd Alexander R, Barbachyn Michael R
Аннотация
QPT-1 was discovered in a compound library by high-throughput screening and triage for substances with whole-cell antibacterial activity. This totally synthetic compound is an unusual barbituric acid derivative whose activity resides in the (-)-enantiomer. QPT-1 had activity against a broad spectrum of pathogenic, antibiotic-resistant bacteria, was nontoxic to eukaryotic cells, and showed oral efficacy in a murine infection model, all before any medicinal chemistry optimization. Biochemical and genetic characterization showed that the QPT-1 targets the beta subunit of bacterial type II topoisomerases via a mechanism of inhibition distinct from the mechanisms of fluoroquinolones and novobiocin. Given these attributes, this compound represents a promising new class of antibacterial agents. The success of this reverse genomics effort demonstrates the utility of exploring strategies that are alternatives to target-based screens in antibacterial drug discovery.