Abstract
Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.
Highlights
Multidrug resistant (MDR) infections in the clinic are growing at a significant rate, largely due to the limited number of bacterial targets inhibited by the arsenal of antibiotics used for the last half-century [1,2,3]
We focused on the highly conserved regions of the two targets, regions with polar character, to design compounds with both enzymatic potency and physicochemical properties profiles needed for Gram-negative antibacterial activity
Based on an analysis of the binding modes of fragment hits on Enterococcus faecalis GyrB, a pyrrolopyrimidine scaffold was deemed an appealing candidate for optimization because it projected synthetic vectors towards all the highly conserved sub-pockets of the GyrB and ParE active-sites including a site for the introduction of charged functionality [15] (Figure 1)
Summary
Multidrug resistant (MDR) infections in the clinic are growing at a significant rate, largely due to the limited number of bacterial targets inhibited by the arsenal of antibiotics used for the last half-century [1,2,3]. To provide potential solutions to this problem, we used structurebased drug design (SBDD) to develop a novel class of broadspectrum antibacterial agents with activity against resistant pathogens, including Gram-negative MDR strains. Frequently mediated by mutations in the drugbinding site, is increasingly limiting the utility of this antibiotic class [6], prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes This has led to substantial activity by many groups focused on the development of inhibitors targeting the ATPase sites on GyrB and ParE [7]. We have succeeded in creating a novel Tricyclic class of GyrB/ParE dual-targeting pyrimidoindole inhibitors (TriBE inhibitors) with potent, broad-spectrum antibacterial activity against a wide range of bacterial pathogens that include drug resistant strains of Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Several lead compounds have been generated, including representative inhibitors described
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