FARM: Forecasting Antibiotic Resistance in Mycobacterium tuberculosis using biophysics and machine learning

Antibiotic-resistant tuberculosis remains a major public health challenge, and rapid diagnosis of resistant infections based on genomic markers holds promise for improving time to effective treatment. However, the vast majority of clinically observed variants in resistance-associated genes remain of uncertain significance, limiting the utility of predictors. Here we develop a multimodal forecasting framework, FARM (Forecasting Antibiotic Resistance in Mycobacterium tuberculosis) to determine whether a newly observed mutation in a resistance gene may indeed cause resistance. Our framework combines structural context, biophysical energy features, protein language model features, and mutational AAIndex physicochemical descriptors. Using 345 labeled mutations from the World Health Organization 2021 catalogue, we train interpretable models that distinguish resistance-associated from non-resistance-associated variants with holdout AUCs of 0.843-0.943. In a novel temporal evaluation of 62 mutations reclassified after the training data was released, the selected Combined model achieved 80.7% recall of resistant reclassifications (resistant-class F1=86.8; AUC=0.735). Applied to 4,525 current uncertain-significance mutations, the framework prioritizes 696 candidate resistance mutations, including genes associated with the new antibiotics bedaquiline, delamanid, and pretomanid. These forecasts are intended to support future catalogue updates and experimental follow-up.