Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity

Tari, Leslie W.; Trzoss, Michael; Bensen, Daniel C.; Li, Xiaoming; Chen, Zhiyong; Lam, Thanh; Zhang, Junhu; Creighton, Christopher J.; Cunningham, Mark L.; Kwan, Bryan; Stidham, Mark A.; Shaw, Karen Joy; Lightstone, Felice C.; Wong, Sergio E.; Nguyen, Toan B.; Nix, Jay C.; Finn, John M.

doi:10.1016/j.bmcl.2012.11.032

Cited by 98 publications

(64 citation statements)

References 9 publications

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“…Similar to the “needle” screen conducted by scientists at Roche [14], low molecular weight fragments with adjacent hydrogen-bond donor/acceptor moieties that engage the ATP adenine-binding aspartate and structural water in the active-site pocket were selected for screening [15]. 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). …”

Section: Resultsmentioning

confidence: 99%

“…C1 ) that had both the desired broad enzymatic spectrum and dual-targeting enzymatic profile by expanding the scaffold into the lipophilic interior of the GyrB and ParE active-sites [15,16] (Figure 1). However, activity against Gram-negative pathogens was limited and we ultimately exhausted avenues for improving potency at the enzyme level without elevating compound molecular weight and lipophilicity to a degree that further compromised Gram-negative antibacterial activity and spectrum.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2013

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

et al. 2013

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“…Structurally related imidazolopyridine and triazolopyridine analogues with potent biochemical and antibacterial activity have also been described (24,25). Alternative chemotypes with dual targeting activity have been reported by other workers (26)(27)(28)(29) We have synthesized a series of benzothiazole ethyl urea compounds as inhibitors of both DNA gyrase and topoisomerase IV. In the present study, the biochemical, antibacterial, and pharmacokinetic evaluation of two representative compounds, designated compound A and compound B, is described.…”

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Biological Evaluation of Benzothiazole Ethyl Urea Inhibitors of Bacterial Type II Topoisomerases

Stokes¹,

Thomaides-Brears²,

Barker³

et al. 2013

Antimicrob Agents Chemother

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bThe type II topoisomerases DNA gyrase (GyrA/GyrB) and topoisomerase IV (ParC/ParE) are well-validated targets for antibacterial drug discovery. Because of their structural and functional homology, these enzymes are amenable to dual targeting by a single ligand. In this study, two novel benzothiazole ethyl urea-based small molecules, designated compound A and compound B, were evaluated for their biochemical, antibacterial, and pharmacokinetic properties. The two compounds inhibited the ATPase activity of GyrB and ParE with 50% inhibitory concentrations of <0.1 g/ml. Prevention of DNA supercoiling by DNA gyrase was also observed. Both compounds potently inhibited the growth of a range of bacterial organisms, including staphylococci, streptococci, enterococci, Clostridium difficile, and selected Gram-negative respiratory pathogens. MIC 90 s against clinical isolates ranged from 0.015 g/ml for Streptococcus pneumoniae to 0.25 g/ml for Staphylococcus aureus. No cross-resistance with common drug resistance phenotypes was observed. In addition, no synergistic or antagonistic interactions between compound A or compound B and other antibiotics, including the topoisomerase inhibitors novobiocin and levofloxacin, were detected in checkerboard experiments. The frequencies of spontaneous resistance for S. aureus were <2.3 ؋ 10 ؊10 with compound A and <5.8 ؋ 10؊11 with compound B at concentrations equivalent to 8؋ the MICs. These values indicate a multitargeting mechanism of action. The pharmacokinetic properties of both compounds were profiled in rats. Following intravenous administration, compound B showed approximately 3-fold improvement over compound A in terms of both clearance and the area under the concentration-time curve. The measured oral bioavailability of compound B was 47.7%.

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“…Among them, coumarins (5) and cyclothialidines (6) inhibit ATPase activity, and quinolones (7), CcdB (8), and microcin B17 (9) arrest the gyrase-DNA covalent complex. Several other compounds inhibit the enzyme activity (10)(11)(12)(13)(14)(15). Among all of these molecules, fluorine substituted quinolones (FQs) act as bactericidal agents by poisoning the gyrase-DNA complex.…”

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Molecular Basis for the Differential Quinolone Susceptibility of Mycobacterial DNA Gyrase

Kumar

Madhumathi

Nagaraja

2014

Antimicrob Agents Chemother

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b DNA gyrase is a type II topoisomerase that catalyzes the introduction of negative supercoils in the genomes of eubacteria. Fluoroquinolones (FQs), successful as drugs clinically, target the enzyme to trap the gyrase-DNA complex, leading to the accumulation of double-strand breaks in the genome. Mycobacteria are less susceptible to commonly used FQs. However, an 8-methoxysubstituted FQ, moxifloxacin (MFX), is a potent antimycobacterial, and a higher susceptibility of mycobacterial gyrase to MFX has been demonstrated. Although several models explain the mechanism of FQ action and gyrase-DNA-FQ interaction, the basis for the differential susceptibility of mycobacterial gyrase to various FQs is not understood. We have addressed the basis of the differential susceptibility of the gyrase and revisited the mode of action of FQs. We demonstrate that FQs bind both Escherichia coli and Mycobacterium tuberculosis gyrases in the absence of DNA and that the addition of DNA enhances the drug binding. The FQs bind primarily to the GyrA subunit of mycobacterial gyrase, while in E. coli holoenzyme is the target. The binding of MFX to GyrA of M. tuberculosis correlates with its effectiveness as a better inhibitor of the enzyme and its efficacy in cell killing. The DNA gyrase is an essential enzyme responsible for the maintenance of DNA topology in eubacteria. The enzyme catalyzes ATP-dependent negative supercoiling of relaxed circular DNA (1). It is composed of two GyrA and two GyrB subunits resulting in a heterotetrameric holoenzyme. Negative supercoiling by DNA gyrase involves a series of sequential events. The enzyme cleaves duplex DNA through which another segment of the same DNA molecule is transferred. The cleaved DNA is resealed followed by the release of substrate DNA, completing one round of DNA supercoiling (2-4). Owing to its indispensability for bacterial survival and its absence in mammals, gyrase has been a much sought-after drug target, culminating in the characterization of a number of inhibitors with diverse mechanisms of action. Among them, coumarins (5) and cyclothialidines (6) inhibit ATPase activity, and quinolones (7), CcdB (8), and microcin B17 (9) arrest the gyrase-DNA covalent complex. Several other compounds inhibit the enzyme activity (10-15). Among all of these molecules, fluorine substituted quinolones (FQs) act as bactericidal agents by poisoning the gyrase-DNA complex. Arrest of gyrase-DNA covalent complex leads to the accumulation of double-strand DNA breaks, triggering the activation of SOS pathways, depletion of reducing equivalents, and generation of reactive oxygen intermediates causing cell death (16,17). Due to this potent bactericidal effect, FQs are used for the treatment of a wide range of bacterial infections (18).Among all bacterial infections, tuberculosis (TB) continues to pose a major global challenge. The treatment of TB includes a combination of several drugs. FQs are now used to treat infection caused by rifampin-resistant tubercle bacilli (19). Although DNA gyrase from many path...

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Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity

Cited by 98 publications

References 9 publications

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

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

Biological Evaluation of Benzothiazole Ethyl Urea Inhibitors of Bacterial Type II Topoisomerases

Molecular Basis for the Differential Quinolone Susceptibility of Mycobacterial DNA Gyrase

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