Discovery and characterization of QPT-1, the progenitor of a new class of bacterial topoisomerase inhibitors.
نویسندگان
چکیده
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.
منابع مشابه
Design, Synthesis and Cytotoxicity Evaluation of New 2-Aryl-5,6-Dihydropyrrolo[2, 1-a]Isoquinoline Derivatives as Topoisomerase Inhibitors
Two set of 2-aryl-5,6-dihydropyrrolo[2,1-a] isoquinolines were designed and synthesized to evaluate their biological activities as topoisomerase inhibitors. Cytotoxic activity of the synthesized compounds 4a-e and 7a-d was assessed against several human cancer cell lines, including MCF-7 (breast cancer cell), HepG2 (liver hepatocellular cells), A549 (adenocarcinomic human alveolar basal epithel...
متن کاملDesign, Synthesis and Cytotoxicity Evaluation of New 2-Aryl-5,6-Dihydropyrrolo[2, 1-a]Isoquinoline Derivatives as Topoisomerase Inhibitors
Two set of 2-aryl-5,6-dihydropyrrolo[2,1-a] isoquinolines were designed and synthesized to evaluate their biological activities as topoisomerase inhibitors. Cytotoxic activity of the synthesized compounds 4a-e and 7a-d was assessed against several human cancer cell lines, including MCF-7 (breast cancer cell), HepG2 (liver hepatocellular cells), A549 (adenocarcinomic human alveolar basal epithel...
متن کاملRho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension
In an elegant example of bench-to-bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of intraocular pressure (IOP) regulation. The critical discovery that pharmacologic manipulation of the cytoskeleton of outflow pathway cells dec...
متن کاملTopoisomerase Inhibitors and Types of Them
Objective: In this paper, we have introduced topoisomerase inhibitors, mechanism of action and types of them. DNA topoisomerases are ubiquitous enzymes that catalyze essential enzymes to solve the topological problems accompanying key nuclear processes such as DNA replication, transcription, repair and chromatin assembly by introducing temporary single or double strand breaks in the DNA. Result...
متن کاملTopoisomerase Inhibitors and Types of Them
Objective: In this paper, we have introduced topoisomerase inhibitors, mechanism of action and types of them. DNA topoisomerases are ubiquitous enzymes that catalyze essential enzymes to solve the topological problems accompanying key nuclear processes such as DNA replication, transcription, repair and chromatin assembly by introducing temporary single or double strand breaks in the DNA. Result...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Antimicrobial agents and chemotherapy
دوره 52 8 شماره
صفحات -
تاریخ انتشار 2008