Dataset Information

Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides.

ABSTRACT: Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont, Wolbachia, for survival and fecundity, making Wolbachia a promising therapeutic target. Here we perform a high-throughput screen of AstraZeneca's 1.3 million in-house compound library and identify 5 novel chemotypes with faster in vitro kill rates (<2 days) than existing anti-Wolbachia drugs that cure onchocerciasis and lymphatic filariasis. This industrial scale anthelmintic neglected tropical disease (NTD) screening campaign is the result of a partnership between the Anti-Wolbachia consortium (A?WOL) and AstraZeneca. The campaign was informed throughout by rational prioritisation and triage of compounds using cheminformatics to balance chemical diversity and drug like properties reducing the chance of attrition from the outset. Ongoing development of these multiple chemotypes, all with superior time-kill kinetics than registered antibiotics with anti-Wolbachia activity, has the potential to improve upon the current therapeutic options and deliver improved, safer and more selective macrofilaricidal drugs.

SUBMITTER: Clare RH

PROVIDER: S-EPMC6315057 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides.

Clare Rachel H RH Bardelle Catherine C Harper Paul P Hong W David WD Börjesson Ulf U Johnston Kelly L KL Collier Matthew M Myhill Laura L Cassidy Andrew A Plant Darren D Plant Helen H Clark Roger R Cook Darren A N DAN Steven Andrew A Archer John J McGillan Paul P Charoensutthivarakul Sitthivut S Bibby Jaclyn J Sharma Raman R Nixon Gemma L GL Slatko Barton E BE Cantin Lindsey L Wu Bo B Turner Joseph J Ford Louise L Rich Kirsty K Wigglesworth Mark M Berry Neil G NG O'Neill Paul M PM Taylor Mark J MJ Ward Stephen A SA

Nature communications 20190102 1

Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont, Wolbachia, for survival and fecundity, making Wolbachia a promising therapeutic target. Here we perform a high-throughput screen of AstraZeneca's 1.3 million in-house compound library and identify 5 novel chemotypes with faster in vitro kill rates (<2 days) than existing anti-Wolbachia drugs that cure onchocerciasis and lymphatic filariasis. This industrial scale anthelmintic neglected tropical diseas ...[more]

PMID: 30602718

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Project description:The prevalence of lung disease due to infections with nontuberculous mycobacteria (NTM) has been increasing and surpassed tuberculosis (TB) in some countries. Treatment outcomes are often unsatisfactory, highlighting an urgent need for new anti-NTM medications. Although NTM in general do not respond well to TB specific drugs, the similarities between NTM and Mycobacterium tuberculosis at the molecular and cell structural level suggest that compound libraries active against TB could be leveraged for NTM drug discovery. Here we tested this hypothesis. The Pathogen Box from the Medicines for Malaria Venture (MMV) is a collection of 400 diverse drug-like compounds, among which 129 are known to be active against M. tuberculosis. By screening this compound collection against two NTM species, Mycobacterium abscessus and Mycobacterium avium, we showed that indeed the hit rates for NTM among TB active compounds is significantly higher compared to compounds that are not active against TB. MIC/dose response confirmation identified 10 top hits. Bactericidal activity determination demonstrated attractive potency for a subset of the confirmed hits. In vivo pharmacokinetic profiling showed that some of the compounds present reasonable starting points for medicinal chemistry programs. Three of the top hits were oxazolidinones, suggesting the potential for repositioning this class of protein synthesis inhibitors to replace linezolid which suffers from low potency. Two hits were inhibitors of the trehalose monomycolate transporter MmpL3, suggesting that this transmembrane protein may be an attractive target for NTM. Other hits are predicted to target a range of functions, including cell division (FtsZ), DNA gyrase (GyrB), dihydrofolate reductase, RNA polymerase and ABC transporters. In conclusion, our study showed that screening TB active compounds for activity against NTM resulted in high hit rates, suggesting that this may be an attractive approach to kick start NTM drug discovery projects. In addition, the work identified a series of novel high value NTM hits with associated candidate targets which can be followed up in hit-to-lead projects for the discovery of new NTM antibiotics.

Dataset Information

Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides.

Publications

Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides.

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