Project ORCHID to identify new compounds in fight against TB

Project ORCHID (Open Collaborative Model for Tuberculosis Lead Optimisation) has kick-started the fight against the spread of multi-drug-resistant TB – responsible for more than one million deaths each year – through the development of a set of methods and tools that has helped to reduce the time it takes to identify potential new medicines. The research is already yielding results, with clinical trials of one potential candidate compound beginning shortly.

Current treatment for TB requires a combination of three or four drugs for six months, which can cause significant side effects. Moreover, the effectiveness of first-line TB chemotherapy has been compromised by the emergence of drug-resistant TB.

To address this issue, the ORCHID alliance led by Dr David Barros of GSK has embarked on a €10m four-year project to develop new medicines against drug-resistant TB and bring them to market in a fast and efficient way.

'When ORCHID started, the last anti-tubercular drug (Rifampin) to be approved was back in the 1960s,' says Barros. 'Efforts to discover new drugs for TB have been very fragmented and academic institutions have been conducting independent research with little or no links to the pharmaceutical industry.'

This structure has, unsurprisingly, been inadequate in delivering novel anti-tubercular drugs. ORCHID is looking to streamline the R&D process with the development of a set of new tools that could cut the typical time it takes for a medicine to reach trial stage from 10 to four years.

By concentrating on both new drugs and compounds already in the clinic, ORCHID has optimised its chances of delivering candidate compounds for clinical trials within this short time frame. The consortium is thus working on several chemical series at different stages of the drug discovery process. Their work has involved: identifying new chemical hits from a screen of the GSK compound collection; optimising compounds that have the potential to replace Isoniazid as InhA inhibitors; and repurposing antibiotic compounds that were previously thought to be ineffective as treatment for TB.

We hope that the imminent clinical trials will ultimately function as a proof of concept

After only two-and-a-half years of research, the team has identified an orally administered β-lactam as a potential candidate to combat TB. The most promising β-lactam will shortly begin clinical trials. Additionally, two new direct inhibitors of InhA have been identified, offering potential replacements for two of the main drugs used in general TB treatment.

In addition, one of the organisations involved in the project, École Polytechnique Fédérale de Lausanne (EPFL), has developed a novel tool that enables single cell time-lapse microscopy. This technique helps in understanding how individual bacteria grow, multiply and die when exposed to drugs.

ORCHID's members are currently negotiating an extension of the project.

'We hope that the imminent clinical trials will ultimately function as a proof of concept,' says Barros.

'If successful, they could fundamentally change the existing paradigm that β-lactams are ineffective against TB. Eventually, we hope that our success can inspire others within the research community to join forces to develop innovative new drugs in the fight against TB.'