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

Abstract

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.

Small-Molecule Antibiotic Drug Development: Need and Challenges

“…(2) Combinations could be used to address bacteria that are in different physiological states, such as actively dividing cells and tolerant bacteria in low-activity states . Such distinct subpopulations of bacteria may have largely nonoverlapping vulnerabilities and targeting them with distinct drugs is already a common strategy for treating tuberculosis . (3) Combinations may reduce the rate of resistance generation, where targets of single antibacterial drugs can rapidly acquire mutations that confer resistance.…”

“… 78 Such distinct subpopulations of bacteria may have largely nonoverlapping vulnerabilities and targeting them with distinct drugs is already a common strategy for treating tuberculosis. 79 (3) Combinations may reduce the rate of resistance generation, where targets of single antibacterial drugs can rapidly acquire mutations that confer resistance. Consideration of strategies to impede the evolution of resistance will be critical for protecting existing and novel antibiotics, and drug combinations already play this role in treatment of tuberculosis, malaria, and HIV/AIDS.…”

Nα‐Aroyl‐N‐Aryl‐Phenylalanine Amides: A Promising Class of Antimycobacterial Agents Targeting the RNA Polymerase

“…[11] Although advances have been made recently, treatment of TB [12] and NTM infections [13] still requires multidrug regimens of several months, because the pathogens occupy various infection niches with diverse microenvironments. [14] Monotherapies can also accelerate the development of drug resistance. [15] Rifamycins are a class of antibiotics that are particularly effective against mycobacteria.…”