Fig. 5: Mathematical modeling of the role of trehalose catalytic shift in the emergence of drug tolerance and drug resistance in Mtb.
A The schematic diagram illustrates a phenotypic transition model in which drug-sensitive population (gray) evolve into drug-resistant population (black) via the formation of drug-tolerant population (red). In this model, bacilli can reversibly switch between drug-sensitive and drug-tolerant states during the intermittent antibiotic treatment. Once a population becomes drug-tolerant, it remains in that state for multiple generations before reverting to a drug-sensitive state. After prolonged antibiotic exposure, each drug-tolerant bacillus irreversibly transitions to drug-resistant state and replicate. To assess the impact of the trehalose-catalytic shift on the frequency of each transition step, wildtype M. smegmatis and ItreSSM were utilized in a fluctuation assay as depicted in Fig. S6A. The reversibility and transition capacities were calculated as described in the Mathematical Modeling section in the “Methods”. Schematic diagram was created in BioRender. Lee, J. (2025) https://BioRender.com/otwhxsl. B The rates of formation of drug-resistant mutants in wildtype and ItreSSM against RIF were determined using the classical Luria-Delbrück fluctuation assay and the Lea-Coulson method (m/Nt, where m is the number of resistant colonies and Nt is the total input). Data points represent mean values ± s.e.m. of biological triplicates for the short-term exposure and 60 biological replicates for the long-term exposure. p-values were determined by Student’s unpaired t test with Welch’s correction. Source data are provided as a Source Data File.
