Identification and prioritization of novel anti-Wolbachia chemotypes from screening a 10,000-compound diversity library.

Abstract:

:Lymphatic filariasis and onchocerciasis are two important neglected tropical diseases (NTDs) that cause severe disability. Control efforts are hindered by the lack of a safe macrofilaricidal drug. Targeting the Wolbachia bacterial endosymbionts in these parasites with doxycycline leads to a macrofilaricidal outcome, but protracted treatment regimens and contraindications restrict its widespread implementation. The Anti-Wolbachia consortium aims to develop improved anti-Wolbachia drugs to overcome these barriers. We describe the first screening of a large, diverse compound library against Wolbachia. This whole-organism screen, streamlined to reduce bottlenecks, produced a hit rate of 0.5%. Chemoinformatic analysis of the top 50 hits led to the identification of six structurally diverse chemotypes, the disclosure of which could offer interesting avenues of investigation to other researchers active in this field. An example of hit-to-lead optimization is described to further demonstrate the potential of developing these high-quality hit series as safe, efficacious, and selective anti-Wolbachia macrofilaricides.

journal_name

Sci Adv

journal_title

Science advances

authors

Johnston KL,Cook DAN,Berry NG,David Hong W,Clare RH,Goddard M,Ford L,Nixon GL,O'Neill PM,Ward SA,Taylor MJ

doi

10.1126/sciadv.aao1551

subject

Has Abstract

pub_date

2017-09-27 00:00:00

pages

eaao1551

issue

9

issn

2375-2548

pii

aao1551

journal_volume

3

pub_type

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