Project: NOvel STRAtegy for Drug discovery by A Microbiome-based approach: Use of PathoGut™ for predictive antibiotic Screening
Clostridium difficile (Cdif) is a Gram positive, spore-forming, anaerobic bacterium that colonizes the intestinal tract and produces toxins, thereby leading to pathological conditions which range from mild diarrhea to life-threatening pseudomembranous colitis. Cdif can cause infection when the balance of the normal gut microbiota is disturbed by the use of any type of antimicrobial agent. Alarmingly, the prevalence and severity of Cdif infections (CDI) are increasing and the associated morbidity and mortality rates are rising. Accordingly, CDI adds significant costs and burden to the healthcare system. CDI can be estimated to potentially cost the European Union €3.000 million per year and it is expected to almost double over the next four decades (European Centre for Disease Prevention and Control). While antibiotics are available to treat CDI, the typical first-line treatments (i.e. metronidazole and vancomycin) have the disadvantage of further microbial disruption of the indigenous microbiota [1] and are associated with recurrent disease [2]. _x000D__x000D_Ideal drugs for treating CDI should: _x000D_i. be only partially or not absorbed and reach high levels of active drug in the colon; _x000D_ii. be highly effective against Cdif with minimal disturbance of intestinal microbiota;_x000D_iii. select resistant mutants at low frequency._x000D_In recent years, a number of antimicrobial agents have been evaluated for management of CDI, but none of them seem to meet the criteria defined above. Although fidaxomicin possesses a reduced antimicrobial spectrum, further comparative evaluation for superiority to vancomycin and metronidazole is needed [3]. Fecal bacteriotherapy has been proposed as a promising alternative treatment for CDI, yet its application reCOs scarce due to concerns of safety (pathogen transfer) and acceptability. Consequently, new therapeutic options for the management of CDI are sorely needed. _x000D__x000D_This project proposal represents an integrated approach for the discovery and screening of drug candidates for CDI based on two innovative technologies. Naicons, an Italian SME aiming at the discovery and development of new drug candidates, has recently started the development of a technology (Thiopeptide Technology) to generate analogs of the antibiotic thiopeptide GE2270 through a combination of synthetic biology and chemical modification. ProDigest is a Belgian SME developing high-level in vitro laboratory model systems of the human intestinal tract. In this project, ProDigest will develop a novel gut model, called PathoGut™, for in vitro screening of antibacterial drug candidates. The PathoGut model will allow to predict the stability, absorption rate, efficacy, selectivity and side-effects of antibiotics in a healthy and disturbed human gastrointestinal tract. Ultimately, both technology platforms – the Thiopeptide Technology and PathoGut - will be integrated to develop a drug with ideal properties for CDI treatment that is ready for Investigational New Drug (IND)-enabling studies, i.e. the final set of formal pharmacology and toxicology studies which are to be performed before the drug candidate can enter clinical evaluation._x000D__x000D_The objectives of this project are:_x000D_1. The development and use of i) the Thiopeptide Technology to generate GE2270 analogs and ii) the PathoGut model for in vitro screening of GE2270 analogs and selection of one or more drug candidates for CDI treatment for further formal preclinical assessment and clinical validation_x000D_2. In vivo validation study using a mouse model of CDI to confirm i) the efficacy of the selected CDI drug candidate and ii) the relevance and predictability of the PathoGut model to screen antibacterial drug candidates for CDI._x000D__x000D_The results of the project will result in three marketable applications;_x000D_1. PathoGut™ will be marketed by ProDigest as part of its contract research platform technology as a highly predictable and validated in vitro screening tool for antibacterial drug candidates in terms of stability, absorption rate, efficacy and impact on the gut microbiome._x000D_2. Thiopeptide Technology will be marketed by Naicons as a technology platform to expand the chemical space in thiopeptide variants for pharmaceutical and other applications._x000D_3. The CDI drug candidate will be available for out-licensing to pharmaceutical companies by Naicons and ProDigest. To reach efficient commercialisation, an exploitation plan will be developed at the end of the project.
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Acronym
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NOSTRADAMUS
(Reference Number: 8404)
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Duration
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01/10/2013 - 30/09/2016
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Project Topic
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NOSTRADAMUS involves an novel approach for drug discovery and screening based on: 1) in vitro PathoGut™ model to study pathogen infection and treatment; 2) Thiopeptide Technology to expand the chemical space in thiopeptide variants. As case study, Clostridium difficile infection was selected.
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Network
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Eurostars
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Call
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Eurostars Cut-Off 10
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Project partner
