ORCHID

Open Collaborative Model for Tuberculosis Lead Optimisation

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 Obiettivo del progetto (Objective)

'Early stage Drug Discovery efforts over the last 5 years have resulted in the identification of a number of promising lead compounds in the fight against TB. These leads need to be further progressed and optimised into candidates for pre-clinical development through the Drug Development progression cascade.

Three compound families are of particular interest: 1) InhA Inhibitors, 2) New potent whole cell anti-tubercular compounds with unknown mode of action and 3) new Beta-lactam/Beta-lactamase combinations for TB. A preclinical package is already in place for some of them, but further work is necessary for others in order to justify the progression of a single anti-tubercular family to the more resource intensive stages of preclinical and clinical development.

The project will encompass the parallel progression of the three compound families through: A) Lead Optimization Chemistry efforts and MoA studies (Genetic and Proteomic) for whole cell inhibitors, B) In vitro and in vivo evaluation of a new orally bioavailable Beta-lactam alone or in combination with a Beta-lactamase inhibitor to evaluate the sterilising potential of the new drug/s and C) the optimization of an InhA inhibitor for later preclinical development.

These efforts will yield candidate molecules for new 'information rich' in vitro assays of antimycobacterial activity (artificial granuloma, activity against slow/non growing cells and activity against clinical isolates) as well as for in vivo safety and efficacy evaluation in different animal models of infection (acute and/or chronic). At this stage a single compound family will be prioritized.

Further studies will be performed assessing the potential for shortening treatment in stand alone therapy as well as in combination regimens both in vitro and in vivo. Finally a Clinical Development plan will be put in place for the selected candidate molecule.'

Introduzione (Teaser)

Tuberculosis (TB) continues to pose a serious health issue in many countries, with millions of new sufferers every year. Although disease incidence is decreasing, there is still an urgent need for novel drugs that combine specificity with efficacy.

Descrizione progetto (Article)

Current treatments for TB present with side-effects and often result in the emergence of multidrug resistant (MDR) TB which requires second generation drugs. These drugs are expensive and are administered via the parenteral route, making it difficult for patients to adhere to therapy. Furthermore, misuse of second generation drugs to treat MDR-TB has resulted in extremely drug resistant TB (XDR-TB) variants that are often beyond chemotherapeutic intervention.

In answer to this problem, the EU-funded 'Open collaborative model for tuberculosis lead optimisation' (http://projectorchid.org/ (ORCHID)) project set out to discover novel lead compounds that could be used in the clinic to treat resistant forms of TB. The work of the ORCHID consortium was based on promising lead compounds identified by Early stage Drug Discovery efforts at a leading biotech company. Partners wished to optimise these candidate molecules and send them for pre-clinical development.

During the ORCHID project, the work focused on three compound families namely InhA Inhibitors, new beta-lactam combinations for TB as well as novel compounds. High-throughput screening of an extensive compound library led to the identification of novel anti-tubercular compounds against the essential mycobacterial protein MmpL3.

With respect to the identification of direct InhA inhibitors, the consortium developed a novel platform for screening DNA-encoded small molecule libraries. In combination with nanotechnology, this platform could assist in the discovery of drugs with enhanced bioavailability, solubility and stability.

Considerable part of the ORCHID work was based on basic research to identify the specificity of some beta-lactam compounds for L,D-transpeptidase. The latter is a key enzyme implicated in peptidoglycan cross-linking and constitutes an active target against M.tuberculosis. Particular emphasis was given to carbapenems due to their proven efficacy against MDR-TB in combination therapy regimens.

Taken together, the ORCHID-identified candidate molecules provide alternative drugs for a shorter and more specific treatment against TB. Most importantly, as they are designed against resistant forms of the disease they offer hope to the millions of afflicted individuals in developing countries.