Predicting Chemical Stressor Effects on Conjugative Plasmid Transfer Rates Using Machine Learning

Abstract Chemical stressors in environmental and clinical settings can alter conjugative plasmid transfer, which is a key process driving antibiotic resistance dissemination. However, predicting these effects across chemically diverse compounds is challenging. Here, we compiled and curated data on the effect of chemical stressors on RP4 plasmid transfer, extracting compound identity, concentration, conjugation frequency, and experimental metadata from 73 in vitro studies. Chemicals were characterized by functional use categories and molecular descriptors, including physicochemical properties, MACCS keys, Morgan fingerprints, and extended descriptors from the OCHEM platform (AlvaDesc, Dragon 7, and 3D-shape descriptors). An exhaustive evaluation of 1022 feature set combinations across 3066 models showed that chemical concentration alone provides no meaningful predictive signal (Q2ext <0), whereas integrating Morgan fingerprints substantially improves predictive performance. The best-performing model combined concentration, Morgan fingerprints, and experimental conditions using extreme gradient boosting (XGB), achieving Q2ext = 0.373 on a held-out compound-aware test set and a median Q2ext of 0.319 within the defined applicability domain across 20 independent splits. SHAP analysis revealed that Morgan fingerprints account for 69% of total predictive weight, with quaternary ammonium compounds and long-chain alkyl structures associated with inhibition of conjugation and sulfonamide and amine-containing compounds associated with promotion. These results demonstrate that chemical structural features provide critical information for predicting the chemical modulation of conjugative plasmid transfer. This work highlights that combining chemically informed descriptors with machine learning (ML) anticipates chemical contributions to antibiotic resistance dissemination, providing a scalable framework for the prioritization and risk assessment of chemicals.