Tools to develop antibiotic combinations that target drug tolerance in Mycobacterium tuberculosis

Combination therapy is necessary to treat tuberculosis to decrease the rate of disease relapse and prevent the acquisition of drug resistance, and shorter regimens are urgently needed. The adaptation of Mycobacterium tuberculosis to various lesion microenvironments in infection induces various states of slow replication and non-replication and subsequent antibiotic tolerance. This non-heritable tolerance to treatment necessitates lengthy combination therapy. Therefore, it is critical to develop combination therapies that specifically target the different types of drug-tolerant cells in infection. As new tools to study drug combinations earlier in the drug development pipeline are being actively developed, we must consider how to best model the drug-tolerant cells to use these tools to design the best antibiotic combinations that target those cells and shorten tuberculosis therapy. In this review, we discuss the factors underlying types of drug tolerance, how combination therapy targets these populations of bacteria, and how drug tolerance is currently modeled for the development of tuberculosis multidrug therapy. We highlight areas for future studies to develop new tools that better model drug tolerance in tuberculosis infection specifically for combination therapy testing to bring the best drug regimens forward to the clinic.

Automated summary

Combination therapy is crucial for treating tuberculosis to reduce disease relapse and prevent drug resistance. The different states of Mycobacterium tuberculosis and its tolerance to antibiotics in various lesion microenvironments require lengthy combination therapy. Developing combination therapies that target specific drug-tolerant cells is essential, and new tools are being developed to study drug combinations earlier in the drug development pipeline. This review discusses the factors underlying drug tolerance, how combination therapy targets these bacteria populations, and current modeling of drug tolerance for multidrug therapy in tuberculosis. Future studies should focus on developing better tools to model drug tolerance in tuberculosis infection specifically for combination therapy testing and the advancement of optimal drug regimens to clinical use.