In Vitro Characterization of the Antibacterial Spectrum of Novel Bacterial Type II Topoisomerase Inhibitors of the Aminobenzimidazole Class

Mani, Nagraj; Gross, Christian H.; Parsons, Jonathan D.; Hanzelka, Brian L.; Müh, Ute; Mullin, Steve; Liao, Yusheng; Grillot, Anne‐Laure; Stamos, Dean; Charifson, Paul S.; Grossman, Trudy H.

doi:10.1128/aac.50.4.1228-1237.2006

Cited by 76 publications

(79 citation statements)

References 25 publications

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“…The enzyme assay was performed as previously described (15). The fully assembled heterotetrameric gyrase A 2 B 2 (after the expression of each separate subunit and subsequent reconstitution prior to assay) was used for inhibitor characterization.…”

Section: Methodsmentioning

confidence: 99%

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

Locher

Jones

Hanzelka

et al. 2015

Antimicrob Agents Chemother

101

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dNew drugs to treat drug-resistant tuberculosis are urgently needed. Extensively drug-resistant and probably the totally drugresistant tuberculosis strains are resistant to fluoroquinolones like moxifloxacin, which target gyrase A, and most people infected with these strains die within a year. In this study, we found that a novel aminobenzimidazole, VXc-486, which targets gyrase B, potently inhibits multiple drug-sensitive isolates and drug-resistant isolates of Mycobacterium tuberculosis in vitro (MICs of 0.03 to 0.30 g/ml and 0.08 to 5.48 g/ml, respectively) and reduces mycobacterial burdens in lungs of infected mice in vivo. VXc-486 is active against drug-resistant isolates, has bactericidal activity, and kills intracellular and dormant M. tuberculosis bacteria in a low-oxygen environment. Furthermore, we found that VXc-486 inhibits the growth of multiple strains of Mycobacterium abscessus, Mycobacterium avium complex, and Mycobacterium kansasii (MICs of 0.1 to 2.0 g/ml), as well as that of several strains of Nocardia spp. (MICs of 0.1 to 1.0 g/ml). We made a direct comparison of the parent compound VXc-486 and a phosphate prodrug of VXc-486 and showed that the prodrug of VXc-486 had more potent killing of M. tuberculosis than did VXc-486 in vivo. In combination with other antimycobacterial drugs, the prodrug of VXc-486 sterilized M. tuberculosis infection when combined with rifapentine-pyrazinamide and bedaquiline-pyrazinamide in a relapse infection study in mice. Furthermore, the prodrug of VXc-486 appeared to perform at least as well as the gyrase A inhibitor moxifloxacin. These findings warrant further development of the prodrug of VXc-486 for the treatment of tuberculosis and nontuberculosis mycobacterial infections.

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Section: Methodsmentioning

confidence: 99%

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

Locher

Jones

Hanzelka

et al. 2015

Antimicrob Agents Chemother

101

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“…VRT-125853 and VRT-752586 ( Fig. 1) are representatives of this class of antibacterials that exhibit broad-spectrum antibacterial activities against both susceptible and multidrug-resistant clinical isolates; in addition, the frequencies of spontaneous resistance to these antibacterials in vitro are low, consistent with their novel dual-targeting mechanisms of action (28). Here we present genetic, biochemical, and physiological data that demonstrate their mechanisms of action against Escherichia coli, S. aureus, S. pneumoniae, Enterococcus faecalis, and Haemophilus influenzae and confirm their in vitro dual-targeting activities, as defined by effective inhibition of both gyrase and topo IV at biologically relevant concentrations.…”

mentioning

confidence: 98%

“…VRT-125853 and VRT-752586 are potent inhibitors of both E. coli and S. aureus gyrase and topo IV in enzyme assays (28). In order to demonstrate that this potent inhibition in vitro translated into inhibition of gyrase and topo IV inside bacterial cells, we tested the effects of VRT-125853 and VRT-752586 on the steady-state levels of plasmid supercoiling in E. coli.…”

Section: Vrt-125853 Inhibitsmentioning

confidence: 99%

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Dual Targeting of GyrB and ParE by a Novel Aminobenzimidazole Class of Antibacterial Compounds

Grossman

Bartels

Mullin

et al. 2007

Antimicrob Agents Chemother

Self Cite

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A structure-guided drug design approach was used to optimize a novel series of aminobenzimidazoles that inhibit the essential ATPase activities of bacterial DNA gyrase and topoisomerase IV and that show potent activities against a variety of bacterial pathogens. Two such compounds, VRT-125853 and VRT-752586, were characterized for their target specificities and preferences in bacteria. In metabolite incorporation assays, VRT-125853 inhibited both DNA and RNA synthesis but had little effect on protein synthesis. Both compounds inhibited the maintenance of negative supercoils in plasmid DNA in Escherichia coli at the MIC. Sequencing of DNA corresponding to the GyrB and ParE ATP-binding regions in VRT-125853-and VRT-752586-resistant mutants revealed that their primary target in Staphylococcus aureus and Haemophilus influenzae was GyrB, whereas in Streptococcus pneumoniae it was ParE. In Enterococcus faecalis, the primary target of VRT-125853 was ParE, whereas for VRT-752586 it was GyrB. DNA transformation experiments with H. influenzae and S. aureus proved that the mutations observed in gyrB resulted in decreased susceptibilities to both compounds. Novobiocin resistance-conferring mutations in S. aureus, H. influenzae, and S. pneumoniae were found in gyrB, and these mutants showed little or no cross-resistance to VRT-125853 or VRT-752586 and vice versa. Furthermore, gyrB and parE double mutations increased the MICs of VRT-125853 and VRT-752586 significantly, providing evidence of dual targeting. Spontaneous frequencies of resistance to VRT-752586 were below detectable levels (<5.2 ؋ 10 ؊10 ) for wild-type E. faecalis but were significantly elevated for strains containing single and double target-based mutations, demonstrating that dual targeting confers low levels of resistance emergence and the maintenance of susceptibility in vitro.

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“…The goal of discovering such balanced dual inhibitors was based on the finding by Vertex scientists that the activity of novobiocin against topoisomerase IV (ParC/ParE), which is normally very weak, can be increased 20-fold by a single amino acid change in the enzyme (35). This was pursued at Vertex (63,64,140,232) and resulted in the discovery of aminobenzimidazoles such as VX-752586 (Fig. 5F), which displays potent activity against both enzymes and antibacterial activity against Gram-positive organisms.…”

Section: Single Pharmacophore Multiple Targetsmentioning

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,109

961

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SUMMARY The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.

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In Vitro Characterization of the Antibacterial Spectrum of Novel Bacterial Type II Topoisomerase Inhibitors of the Aminobenzimidazole Class

Cited by 76 publications

References 25 publications

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

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

Dual Targeting of GyrB and ParE by a Novel Aminobenzimidazole Class of Antibacterial Compounds

Challenges of Antibacterial Discovery

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