The Compound TB47 is Highly Bactericidal Against Mycobacterium Ulcerans in a Buruli Ulcer Mouse Model

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Feb 2

PMID 30705268

Citations 22

Authors

Yang Liu

Yamin Gao

Jianxiong Liu

Yaoju Tan

Zhiyong Liu

Chiranjibi Chhotaray

Huofeng Jiang

Zhili Lu

Gift Chiwala

Shuai Wang

Gaelle Makafe

Md Mahmudul Islam

H M Adnan Hameed

Xingshan Cai

Changwei Wang

Xinjie Li

Shouyong Tan

Tianyu Zhang

Affiliations

Soon will be listed here.

Abstract

Buruli ulcer (BU) is an emerging infectious disease that causes disfiguring skin ulcers. The causative agent, Mycobacterium ulcerans, secretes toxin called mycolactone that triggers inflammation and immunopathology. Existing treatments are lengthy and consist of drugs developed for tuberculosis. Here, we report that a pyrazolo[1,5-a]pyridine-3-carboxamide, TB47, is highly bactericidal against M. ulcerans both in vitro and in vivo. In the validated mouse model of BU, TB47 alone reduces M. ulcerans burden in mouse footpads by more than 2.5 log CFU compared to the standard BU treatment regimen recommended by the WHO. We show that mutations of ubiquinol-cytochrome C reductase cytochrome subunit B confer resistance to TB47 and the dissimilarity of CydABs from different mycobacteria may account for their differences in susceptibility to TB47. TB47 is highly potent against M. ulcerans and possesses desirable pharmacological attributes and low toxicity that warrant further assessment of this agent for treatment of BU.

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