Tricyclic GyrB/ParE (TriBE) Inhibitors: A New Class of Broad-Spectrum Dual-Targeting Antibacterial Agents

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.

Mutant Alleles of lptD Increase the Permeability of Pseudomonas aeruginosa and Define Determinants of Intrinsic Resistance to Antibiotics

“…When there is success in attaining cellular bioactivity, close attention must be paid to overcoming intrinsic resistance mechanisms such as efflux and permeability. Such efforts have shown promise in recent years with the development of hydroxamate LpxC inhibitors (84)(85)(86), novel bacterial type II topoisomerase inhibitors (NBTIs) (87,88), tricyclic GyrB/ParE (TriBE) inhibitors (89), and pyrrolocytosine ribosome inhibitors (90). Although these classes of compounds have not yet reached clinical utility, they demonstrate progress and inspire confidence that novel Gram-negative antibiotics can be discovered.…”

A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

“…The catalytic subunits (GyrA/ParC) are clinically validated drug targets of the fluoroquinolones, such as moxifloxacin (MXF) (2), while the ATPase subunits (GyrB/ParE) have not been as extensively exploited and may present a new option for treating DR strains of M. tuberculosis (3). Furthermore, several different chemical classes have been described as inhibitors of gyrase B with potent activity against DR bacteria, including M. tuberculosis (4)(5)(6)(7)(8)(9)(10).…”

Target-Based Resistance in Pseudomonas aeruginosa and Escherichia coli to NBTI 5463, a Novel Bacterial Type II Topoisomerase Inhibitor

“…There have been several reports of novel, nonquinolone compounds that interact with bacterial type II topoisomerases gyrase and topoisomerase IV (TopoIV); however, these are almost exclusively active primarily against Grampositive pathogens, although one class of tricyclic compounds has broader activity (10)(11)(12)(13)(14)(15)(16)(17). We have recently reported on a chemical class of topoisomerase inhibitors with activity against several Gram-negative multidrug resistant pathogens; these compounds have been termed novel bacterial type II topoisomerase inhibitors (NBTI) (11,18).…”