Prediction of bacteria-specific drug metabolism using a cross-attention-based model.

Drug metabolism by gut microorganisms is bacteria-specific and can have clinically significant consequences, including prodrug activation, drug inactivation, and the generation of toxic metabolites. However, existing computational approaches have primarily focused on community-level predictions or drug-to-microbe effects, without resolving the metabolic contributions of individual bacterial strains or the bidirectional nature of drug-bacteria interactions, despite advances in computational frameworks. Here, we propose a bidirectional cross-attention architecture, multimodal Bi-MHA, that integrates atom-level molecular embeddings and protein-level bacterial embeddings from pretrained models to generate a combined representation for classification. The proposed model was developed using reliability stratification and a $\mathrm{\lambda}$-scaled loss function on the training dataset and achieved consistent performance across three unseen tasks: unseen drug (receiver operating characteristic area under the curve [ROC AUC]: 0.690), unseen bacteria (ROC AUC: 0.920), and unseen interaction (ROC AUC: 0.949), ranking first among all compared models in the rank-sum metric. Beyond prediction, attention-based analysis not only indicated enzymatic reaction sites that were experimentally validated in previous studies but also prioritized candidate bacterial proteins, demonstrating interpretability at both the atom and protein levels. The proposed model also achieved a 15 percentage point improvement in accuracy over the KNN baseline on an external validation dataset of 85 out-of-distribution drug-bacteria pairs. Furthermore, the model was extended to community-level prediction as a proof-of-concept application using a weighted-abundance pipeline on an independent microbiome dataset. These results demonstrate the model's potential as an interpretable screening tool for drug safety evaluation and personalized medicine. The source code is available at https://github.com/Jaehyeon-O-Ob/Bacteria-Specific_Drug_Metabolism.