ABP-Xplorer: A Machine Learning Approach for Prediction of Antibacterial Peptides Targeting Mycobacterium abscessus-tRNA-Methyltransferase (TrmD).

Abstract

Mycobacterium abscessus (MAB) infections pose a significant treatment challenge due to their intrinsic resistance to antibiotics, requiring prolonged multidrug regimens with limited success and frequent relapses. tRNA (m1G37) methyltransferase (TrmD), an enzyme essential for maintaining the reading frame during protein synthesis in MAB and other mycobacteria, is a potential therapeutic target for identifying new inhibitors. This study introduces ABP-Xplorer, a machine learning-based (ML) model designed to predict the antibacterial potential of peptides targeting MAB-TrmD ribosomal sites. A systematic evaluation of 26 machine learning models identified the Random Forest (RF) classifier as the most effective, achieving 96% accuracy. To address data set imbalance and enhance predictive reliability, the Synthetic Minority Oversampling Technique (SMOTE) was applied, improving model generalization and reducing bias. After that, an ABP-Xplorer streamlit was developed to predict positive and negative antibacterial peptides (ABP), enabling easy sequence input and classification based on predictive scoring. For validation, 12 positive peptides with high predictive scores were selected for molecular docking by HADDOCK. Docking analysis of selected peptides confirmed strong binding to TrmD, with P1, P7, P8, and P9 as top candidates. Notably, P1 exhibited the best interaction with a HADDOCK score of -102.2, followed by P7 (-93.6) and P8 (-91.4), indicating their potential for further development as TrmD inhibitors.Moreover, Ramachandran plot analysis validated the structural reliability. Future research should focus on the experimental validation of these peptides and optimizing their stability and bioavailability for therapeutic applications.