<i>In Vitro</i>
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            <i>In Vivo</i>
            Activities of DS-2969b, a Novel GyrB Inhibitor, against Clostridium difficile

Mathur, Tarun; Barman, Tarani Kanta; Kumar, Manoj; Singh, Diksha; Kumar, Ram; Khera, Manoj Kumar; Yamada, Makiko; Inoue, Shinichi; Upadhyay, Dilip J.; Masuda, Nobuhisa

doi:10.1128/aac.02157-17

Cited by 22 publications

(24 citation statements)

References 23 publications

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“…Our understanding of the human microbiome in health and disease has significantly expanded owing to the establishment of the 16S rRNA gene sequencing of the microbial genomes. The technology has propelled research on microbiome composition and function, as well as it allowed us to understand the effect of various factors in modifying the microbiome composition [39][40][41][42][43].…”

Section: Microbiomics In Ibd: From Postulated Theories To Known Diffementioning

confidence: 99%

Integrating omics for a better understanding of Inflammatory Bowel Disease: a step towards personalized medicine

2019

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Background: Inflammatory Bowel Disease (IBD) is a multifactorial chronic disease. Understanding only one aspect of IBD pathogenesis does not reflect the complex nature of IBD nor will it improve its clinical management. Therefore, it is vital to dissect the interactions between the different players in IBD pathogenesis in order to understand the biology of the disease and enhance its clinical outcomes. Aims:To provide an overview of the available omics data used to assess the potential mechanisms through which various players are contributing to IBD pathogenesis and propose a precision medicine model to fill the current knowledge gap in IBD.Results: Several studies have reported microbial dysbiosis, immune and metabolic dysregulation in IBD patients, however, this data is not sufficient to create signatures that can differentiate between the disease subtypes or between disease relapse and remission. Conclusions:We summarized the current knowledge in the application of omics in IBD patients, and we showed that the current knowledge gap in IBD hinders the improvements of clinical decision for treatment as well as the prediction of disease relapse. We propose one way to fill this gap by implementing integrative analysis of various omics datasets generated from one patient at a single time point.

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Section: Microbiomics In Ibd: From Postulated Theories To Known Diffementioning

confidence: 99%

Integrating omics for a better understanding of Inflammatory Bowel Disease: a step towards personalized medicine

2019

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“…DS-2969b showed in vitro activity against a variety of C. difficile clinical isolates, with an MIC 90 of 0.06 g/ml, which was 2-, 16-, and 32-fold lower than those of fidaxomicin, metronidazole, and vancomycin, respectively (13). DS-2969b demonstrated dose-dependent efficacy in a hamster model of NAP1/027 infection, which was superior to vancomycin or fidaxomicin (13). DS-2969b was safe and well tolerated in preclinical toxicology studies (14).…”

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confidence: 98%

“…DS-2969b has highly specific antimicrobial activity against Gram-positive bacteria, including strict and facultative anaerobes. The activity of DS-2969b was limited to Gram-positive bacteria, with low activity against Gram-negative organisms in the intestinal microbiota (13). DS-2969b showed in vitro activity against a variety of C. difficile clinical isolates, with an MIC 90 of 0.06 g/ml, which was 2-, 16-, and 32-fold lower than those of fidaxomicin, metronidazole, and vancomycin, respectively (13).…”

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confidence: 99%

“…The activity of DS-2969b was limited to Gram-positive bacteria, with low activity against Gram-negative organisms in the intestinal microbiota (13). DS-2969b showed in vitro activity against a variety of C. difficile clinical isolates, with an MIC 90 of 0.06 g/ml, which was 2-, 16-, and 32-fold lower than those of fidaxomicin, metronidazole, and vancomycin, respectively (13). DS-2969b demonstrated dose-dependent efficacy in a hamster model of NAP1/027 infection, which was superior to vancomycin or fidaxomicin (13).…”

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confidence: 99%

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Phase 1 Study To Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Oral Doses of DS-2969b, a Novel GyrB Inhibitor, in Healthy Subjects

Vandell

Inoue

Dennie

et al. 2018

Antimicrob Agents Chemother

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DS-2969b is a novel GyrB inhibitor in development for the treatment of infection (CDI). The aim of this study was to assess the safety, tolerability, pharmacokinetics, and effects on the normal gastrointestinal microbiota of multiple daily oral ascending doses of DS-2969b in healthy subjects. The study enrolled three sequential ascending-dose cohorts (60 mg, 200 mg, and 400 mg). In each cohort, subjects received an oral dose of DS-2969b or placebo (six subjects received DS-2969b, and two received placebo) each morning for 14 days. DS-2969b was safe and well tolerated at all dose levels examined. All adverse events related to DS-2969b were mild and predominantly related to the gastrointestinal tract. DS-2969a (free form of DS-2969b) plasma concentrations increased with increasing doses; however, both the maximum concentration of drug in serum () and the area under the concentration-time curve (AUC) increased less than dose proportionally. In all cohorts, sufficient fecal levels of DS-2969a were achieved within 24 h following the administration of the first dose and maintained for at least 17 days. Following treatment with DS-2969b, clear reductions in the populations of and groups were observed. However, populations of three other bacterial groups examined (, , and) were not affected. Data from this study support and encourage the further development of DS-2969b as a novel treatment for CDI.

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“…DS-2969b ( Fig. 1A) is a new investigational GyrB inhibitor currently under clinical development (26) for the treatment of Clostridium difficile infections. DS11960558 (Fig.…”

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confidence: 99%

In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, and Its Water-Soluble Prodrug, DS11960558, against Methicillin-Resistant Staphylococcus aureus

Barman

Kumar

Mathur

et al. 2018

Antimicrob Agents Chemother

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DS-2969b is a novel GyrB inhibitor under clinical development. In this study, the activity of DS-2969b and the activities of DS-2969b and its water-soluble prodrug, DS11960558, against methicillin-resistant (MRSA) were evaluated. DS-2969b inhibited the supercoiling activity of DNA gyrase and the decatenation activity of its topoisomerase IV. DS-2969b showed antibacterial activity against Gram-positive aerobes but not against Gram-negative aerobes, except for and DS-2969b was active against MRSA with an MIC of 0.25 μg/ml, which was 8-fold lower than that of linezolid. The presence of a pulmonary surfactant did not affect the MIC of DS-2969b. DS-2969b showed time-dependent slow killing against MRSA. The frequency of spontaneous resistance development was less than 6.2 × 10 in all four isolates at 4× MIC of DS-2969b. In a neutropenic MRSA-induced murine muscle infection model, DS-2969b was more efficacious than linezolid by both the subcutaneous and oral routes. DS-2969b and DS11960558 showed efficacy in a neutropenic murine MRSA lung infection model. The pharmacokinetics and pharmacodynamics of DS-2969b and DS11960558 against MRSA were characterized in a neutropenic murine thigh infection model; the percentage of time during the dosing period in which the free drug concentration exceeded the MIC () correlated best with efficacy, and the static percent was 43 to 49%. A sufficient was observed in a phase 1 multiple-ascending-dose study of DS-2969b given orally at 400 mg once a day. These results suggest that DS11960558 and DS-2969b have potential for use as intravenous-to-oral step-down therapy for treating MRSA infections with a higher efficacy than linezolid.

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In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, against Clostridium difficile

Cited by 22 publications

References 23 publications

Integrating omics for a better understanding of Inflammatory Bowel Disease: a step towards personalized medicine

Integrating omics for a better understanding of Inflammatory Bowel Disease: a step towards personalized medicine

Phase 1 Study To Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Oral Doses of DS-2969b, a Novel GyrB Inhibitor, in Healthy Subjects

In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, and Its Water-Soluble Prodrug, DS11960558, against Methicillin-Resistant Staphylococcus aureus

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