Anti-tuberculosis treatment strategies and drug development: challenges and priorities

Despite two decades of intensified research to understand and cure tuberculosis disease, biological uncertainties remain and hamper progress. However, owing to collaborative initiatives including academia, the pharmaceutical industry and non-for-profit organizations, the drug candidate pipeline is promising. This exceptional success comes with the inherent challenge of prioritizing multidrug regimens for clinical trials and revamping trial designs to accelerate regimen development and capitalize on drug discovery breakthroughs. Most wanted are markers of progression from latent infection to active pulmonary disease, markers of drug response and predictors of relapse, in vitro tools to uncover synergies that translate clinically and animal models to reliably assess the treatment shortening potential of new regimens. In this Review, we highlight the benefits and challenges of 'one-size-fits-all' regimens and treatment duration versus individualized therapy based on disease severity and host and pathogen characteristics, considering scientific and operational perspectives. The anti-tuberculosis drug candidate pipeline is promising, but the recent breakthroughs are challenged with the need to prioritize drug combinations for clinical trials and revamping trial designs to accelerate regimen development. In this Review, Dartois and Rubin explore treatment challenges, drug development priorities, and approaches - from basic research to preclinical evaluation - that lead to the selection of drug combinations earlier in the discovery cascade to accelerate the approval of shorter treatment regimens.

Automated summary

Despite two decades of research, uncertainties in understanding and curing tuberculosis disease continue to hinder progress. However, collaborative efforts between academia, the pharmaceutical industry, and non-profit organizations have resulted in a promising drug candidate pipeline. This review explores the challenges and benefits of standardized regimens versus individualized therapy and highlights the need for markers of disease progression, drug response, and predictors of relapse, as well as in vitro tools and animal models for evaluating new regimens. Additionally, it discusses the importance of prioritizing drug combinations for clinical trials and redesigning trial designs to expedite regimen development.