Biological profiling of novel tricyclic inhibitors of bacterial DNA gyrase and topoisomerase IV

Savage, Victoria J.; Charrier, Cédric; Salisbury, Anne‐Marie; Moyo, Emmanuel; Forward, Henry; Chaffer-Malam, Nathan; Metzger, Richard; Huxley, Anthony Julian; Kirk, Ralph; Uosis-Martin, M.; Noonan, Gary M.; Mohmed, Sarfraz; Best, Stuart; Ratcliffe, Andrew J.; Stokes, Neil R.

doi:10.1093/jac/dkw061

Cited by 28 publications

(27 citation statements)

References 25 publications

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“…In summary, the microbiological, pharmacokinetic, and efficacy data presented in this study, and our previous report (10), support the potential of the NTTI compounds as a onceonly oral therapy for the treatment of drug-resistant gonorrhea. …”

supporting

confidence: 85%

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Efficacy of a Novel Tricyclic Topoisomerase Inhibitor in a Murine Model of Neisseria gonorrhoeae Infection

Savage

Charrier

Salisbury

et al. 2016

Antimicrob Agents Chemother

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There is an urgent need for new antibiotics to treat multidrug-resistant Neisseria gonorrhoeae. In this report, the microbiology, in vivo pharmacokinetics, and efficacy of REDX05931, a representative novel tricyclic topoisomerase inhibitor, were evaluated. REDX05931 demonstrated high oral bioavailability in mice and reduced N. gonorrhoeae infection after a single dose in a mouse model of gonorrhea. These data support the potential of this series of small molecules as a new treatment for drug-resistant gonorrheal infections.

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supporting

confidence: 85%

“…Peak plasma concentration (C max ) was achieved within 1 h after p.o. dosing, with values of 1,135.3 and 5,604.0 ng/ml at 5 and 30 mg/kg, respectively, thereby confirming the approximate dose linearity observed with other compounds from this series (10). At 60 mg/kg, C max was obtained at 0.5 h, with a value of 15,597.3 ng/ml.…”

supporting

confidence: 76%

Efficacy of a Novel Tricyclic Topoisomerase Inhibitor in a Murine Model of Neisseria gonorrhoeae Infection

Savage

Charrier

Salisbury

et al. 2016

Antimicrob Agents Chemother

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“…E. coli topoisomerase IV decatenation reactions were conducted under the following conditions: 50 mM HEPES-KOH (pH 7.6), 100 mM potassium glutamate, 10 mM magnesium acetate, 10 mM dithiothreitol, 1 mM ATP, and 50 g/ml BSA. Inhibition of human topoisomerase II decatenation activity was assessed as described previously (14). Reactions were stopped using 30 l chloroform/isoamyl alcohol (26:1) and 20 l stop dye (40% sucrose, 100 mM Tris-HCl [pH 7.5], 1 mM EDTA, 0.5 g/ml bromophenol blue).…”

Section: Methodsmentioning

confidence: 99%

“…Despite the now widespread resistance to the quinolones, the type II topoisomerases continue to provide opportunities for antibacterial discovery based on exploiting novel binding interactions between new chemical ligands and the target enzymes in order to bypass mutations associated with quinolone resistance. Selected examples of this strategy are the 2-aminoquinazolinedione (11), the isothiazoloquinolone (12), the spiropyrimidinetrione (13), and the novel tricyclic topoisomerase inhibitor (NTTI) (14) classes.…”

mentioning

confidence: 99%

Novel Bacterial Topoisomerase Inhibitors with Potent Broad-Spectrum Activity against Drug-Resistant Bacteria

Charrier

Salisbury

Savage

et al. 2017

Antimicrob Agents Chemother

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The novel bacterial topoisomerase inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that does not have cross-resistance with the quinolones. Here, we report the evaluation of the in vitro properties of a new series of this type of small molecule. Exemplar compounds selectively and potently inhibited the catalytic activities of Escherichia coli DNA gyrase and topoisomerase IV but did not block the DNA breakage-reunion step. Compounds showed broad-spectrum inhibitory activity against a wide range of Grampositive and Gram-negative pathogens, including biodefence microorganisms and Mycobacterium tuberculosis. No cross-resistance with fluoroquinolone-resistant Staphylococcus aureus and E. coli isolates was observed. Measured MIC 90 values were 4 and 8 g/ml against a panel of contemporary multidrug-resistant isolates of Acinetobacter baumannii and E. coli, respectively. In addition, representative compounds exhibited greater antibacterial potency than the quinolones against obligate anaerobic species. Spontaneous mutation rates were low, with frequencies of resistance typically Ͻ10 Ϫ8 against E. coli and A. baumannii at concentrations equivalent to 4-fold the MIC. Compound-resistant E. coli mutants that were isolated following serial passage were characterized by whole-genome sequencing and carried a single Arg38Leu amino acid substitution in the GyrA subunit of DNA gyrase. Preliminary in vitro safety data indicate that the series shows a promising therapeutic index and potential for low human ether-a-go-go-related gene (hERG) inhibition (50% inhibitory concentration [IC 50 ], Ͼ100 M). In summary, the compounds' distinct mechanism of action relative to the fluoroquinolones, whole-cell potency, low potential for resistance development, and favorable in vitro safety profile warrant their continued investigation as potential broad-spectrum antibacterial agents.

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“…Although β‐lactams are the only example of successful conversions through the addition of a primary amine that has reached the market, there are a handful of analogous conversions that can be found in the literature. One example is the DNA gyrase/topoisomerase IV inhibitors developed by RedX Pharma . REDX04139 (Fig.…”

Section: Successful Gram‐positive To Gram‐negative Conversionsmentioning

confidence: 99%

The challenge of converting Gram‐positive‐only compounds into broad‐spectrum antibiotics

Richter

Hergenrother

2018

Annals of the New York Academy of Sciences

187

202

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Multidrug resistant Gram-negative bacterial infections are on the rise, and there is a lack of new classes of drugs to treat these pathogens. This drug shortage is largely due to the challenge of finding antibiotics that can permeate and persist inside Gram-negative species. Efforts to understand the molecular properties that enable certain compounds to accumulate in Gram-negative bacteria based on retrospective studies of known antibiotics have not been generally actionable in the development of new antibiotics. A recent assessment of the ability of >180 diverse small molecules to accumulate in Escherichia coli led to predictive guidelines for compound accumulation in E. coli. These "eNTRy rules" state that compounds are most likely to accumulate if they contain a nonsterically encumbered ionizable Nitrogen (primary amines are the best), have low Three-dimensionality (globularity ≤ 0.25), and are relatively Rigid (rotatable bonds ≤ 5). In this review, we look back through 50+ years of antibacterial research and 1000s of derivatives and assess this historical data set through the lens of these predictive guidelines. The results are consistent with the eNTRy rules, suggesting that the eNTRy rules may provide an actionable and general roadmap for the conversion of Gram-positive-only compounds into broad-spectrum antibiotics.

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Biological profiling of novel tricyclic inhibitors of bacterial DNA gyrase and topoisomerase IV

Abstract: Redx Pharma has discovered a novel series of topoisomerase inhibitors that are being further developed for drug-resistant bacteria.

Cited by 28 publications

References 25 publications

Efficacy of a Novel Tricyclic Topoisomerase Inhibitor in a Murine Model of Neisseria gonorrhoeae Infection

Efficacy of a Novel Tricyclic Topoisomerase Inhibitor in a Murine Model of Neisseria gonorrhoeae Infection

Novel Bacterial Topoisomerase Inhibitors with Potent Broad-Spectrum Activity against Drug-Resistant Bacteria

The challenge of converting Gram‐positive‐only compounds into broad‐spectrum antibiotics

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