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Identification of drug candidates that enhance pyrazinamide activity from a clinical drug library

By Hongxia Niu, Luis Alfonso Martinez-Cruz, Peng Cui, Wanliang Shi, Shuo Zhang, Jie Feng, David Sullivan, Bingdong Zhu, Wenhong Zhang, Ying Zhang

Posted 04 Mar 2017
bioRxiv DOI: 10.1101/113704 (published DOI: 10.1038/emi.2017.23)

Tuberculosis (TB) remains a leading cause of morbidity and mortality globally. The current TB therapy takes at least 6 months for drug-susceptible TB and 9-24 months for MDR-TB. The lengthy therapy is thought to be due to M. tuberculosis persisters that are not effectively killed by the current TB drugs. However, pyrazinamide (PZA) is an indispensable frontline TB drug that kills M. tuberculosis persisters and plays a critical role in shortening the treatment. In this study, we explored the idea of identifying FDA-approved drugs that enhance PZA activity as a rapid and efficient approach to developing more effective treatment as opposed to new drug development. To achieve that, we screened the clinical drug library and identified various drug candidates that could enhance PZA activity in vitro against a 3-month-old M. tuberculosis culture. These findings are of particular interest and may have implications for improved treatment of drug-susceptible TB and drug-resistant TB. Further studies are needed to determine if these drugs can shorten TB treatment in vivo in animal models and if so in patients.

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