Abstract
Background/Objectives: Infectious diseases caused by Staphylococcus aureus (S. aureus) have become alarming health issues worldwide due to the ever-increasing emergence of multidrug resistance. In silico approaches can accelerate the identification and/or design of versatile antibacterial chemicals with the ability to target multiple S. aureus strains with varying degrees of drug resistance. Here, we develop a perturbation theory machine learning model based on a multilayer perceptron neural network (PTML-MLP) for the prediction and design of versatile virtual inhibitors against S. aureus strains. Methods: To develop the PTML-MLP model, chemical and biological data associated with antibacterial activity against S. aureus strains were retrieved from the ChEMBL database. We applied the Box-Jenkins approach to convert the topological indices into multi-label graph-theoretical indices; the latter were used as inputs for the creation of the PTML-MLP model. Results: The PTML-MLP model exhibited accuracy higher than 80% in both training and test sets. The physicochemical and structural interpretation of the PTML-MLP model was performed through the fragment-based topological design (FBTD) approach. Such interpretations permitted the analysis of different molecular fragments with favorable contributions to the multi-strain antibacterial activity and the design of four new drug-like molecules using different fragments as building blocks. The designed molecules were predicted/confirmed by our PTML model as multi-strain inhibitors of diverse S. aureus strains, thus representing promising chemotypes to be considered for future synthesis and biological testing of versatile anti-S. aureus agents. Conclusions: This work envisages promising applications of PTML modeling for early antibacterial drug discovery and related antimicrobial research areas.