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Preclinical development of Ramizol, an antibiotic belonging to a new class, for the treatment of Clostridium difficile colitis.

ABSTRACT: Antibiotic-resistant bacteria is a major threat to human health and is predicted to become the leading cause of death from disease by 2050. Despite the recent resurgence of research and development in the area, few antibiotics have reached the market, with most of the recently approved antibiotics corresponding to new uses for old antibiotics, or structurally similar derivatives thereof. We have recently reported an in silico approach that led to the design of an entirely new class of antibiotics for the bacteria-specific mechanosensitive ion channel of large conductance: MscL. Here, we present the preclinical development of one such antibiotic, Ramizol, a first generation antibiotic belonging to that class. We present the lack of interaction between Ramizol and other mammalian channels adding credibility to its MscL selectivity. We determine the pharmacokinetic profile in a rat model and show <0.1% of Ramizol is absorbed systemically. We show this non-systemic nature of the antibiotic translates to over 70% survival of hamsters in a Clostridium difficile colitis model. Lastly, initial in vitro data indicate that resistance to Ramizol occurs at a low frequency. In conclusion, we establish the potential of Ramizol as an effective new treatment for C. difficile associated disease.

SUBMITTER: Rao S

PROVIDER: S-EPMC5399159 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Preclinical development of Ramizol, an antibiotic belonging to a new class, for the treatment of Clostridium difficile colitis.

Rao Shasha S Prestidge Clive A CA Miesel Lynn L Sweeney Deb D Shinabarger Dean L DL Boulos Ramiz A RA

The Journal of antibiotics 20160518 12

Antibiotic-resistant bacteria is a major threat to human health and is predicted to become the leading cause of death from disease by 2050. Despite the recent resurgence of research and development in the area, few antibiotics have reached the market, with most of the recently approved antibiotics corresponding to new uses for old antibiotics, or structurally similar derivatives thereof. We have recently reported an in silico approach that led to the design of an entirely new class of antibiotic ...[more]

PMID: 27189122

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Project description:INTRODUCTION:Clostridium difficile infections (CDI) are common, costly and potentially life threatening. Most CDI will respond to antibiotic therapy, but 3%-10% of all patients with CDI will progress to a severe, life-threatening course. Complete removal of the large bowel is indicated for severe CDI. However, the 30-day mortality following surgical intervention for severe CDI ranges from 20% to 70%. A less invasive approach using surgical faecal diversion and direct colonic lavage with polyethylene glycol (PEG) and vancomycin has demonstrated a relative mortality reduction of approximately 50%. As an alternative to these operative approaches, we propose to treat patients with bedside intestinal lavage with PEG and vancomycin instillation via nasojejunal tube, in addition to usual antibiotic management. Preliminary data collected by our research group are encouraging. METHODS AND ANALYSIS:We will conduct a 1-year, single-centre, pilot randomised controlled trial to study this new treatment strategy for patients with severe CDI and additional risk factors for fulminant or complicated infection. After informed consent, patients with severe-complicated CDI without immediate indication for surgery will be randomised to either usual antibiotic treatment or usual antibiotic treatment with the addition of 8 L of PEG lavage via nasojejunal tube. This pilot trial will evaluate our eligibility and enrolment rate, protocol compliance and adverse event rates and provide further data to inform a more robust sample size calculation and protocol modifications for a definitive multicentre trial design. Based on historical data, we anticipate enrolling approximately 24 patients during the 1-year pilot study period.As a pilot study, data will be reported in aggregate. Between-group differences will be assessed in a blinded fashion for evidence of harm, and to further refine our sample size calculation. ETHICS AND DISSEMINATION:This study protocol has been reviewed and approved by our local institutional review board. Results of the pilot trial and subsequent main trial will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER:NCT02466698; Pre-results.

Dataset Information

Preclinical development of Ramizol, an antibiotic belonging to a new class, for the treatment of Clostridium difficile colitis.

Publications

Preclinical development of Ramizol, an antibiotic belonging to a new class, for the treatment of Clostridium difficile colitis.

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