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

Tuberculosis (TB) remains a leading cause of morbidity and mortality globally despite the availability of the TB therapy. 1 The current TB therapy is lengthy and suboptimal, requiring a treatment time of at least 6 months for drug susceptible TB and 9-12 months (shorter Bangladesh regimen) or 18-24 months (regular regimen) for multi-drug-resistant tuberculosis (MDR-TB). 1 The lengthy therapy makes patient compliance difficult, which frequently leads to emergence of drug-resistant strains. The requirement for the prolonged treatment is thought to be due to dormant persister bacteria which are not effectively killed by the current TB drugs, except rifampin and pyrazinamide (PZA) which have higher activity against persisters. 2, 3 Therefore new therapies should address the problem of insufficient efficacy against M. tuberculosis persisters, which could cause relapse of clinical disease. 4 PZA is a critical frontline TB drug that kills persister bacteria 5 and shortens the TB treatment from 9-12 months to 6 months. 6, 7 Although several new TB drugs are showing promise in clinical studies, none can replace PZA as they all have to be used together with PZA. 7 Because of the essentiality of PZA and the high cost of developing new drugs, in this study, we explored the idea of identifying drugs that enhance the anti-persister activity of PZA as an economic alternative approach to developing new drugs for improved treatment by screening an clinical drug library against old M. tuberculosis cultures enriched with persisters.