In silico drug discovery pipelines targeting antibiotic resistance: from genomes to leads

Abstract

Antimicrobial resistance (AMR) is currently one of the leading global health threats. The evolution of drug-resistant bacterial pathogens is rapid, and there is a growing number of bacterial pathogens that have developed resistance to multiple antibiotics, and the rate at which new antibiotics are being developed is lagging far behind these two issues. In addition, historical drug discovery processes rely on conducting traditional in vitro-based studies to determine new antibiotics to use in practice. However, this process is becoming increasingly constricted due to high costs of conducting traditional in vitro research, lengthy timeframes to bring products to market, a high attrition rate of research projects in traditional wet laboratory environments, and the need for more effective and efficient ways of developing new drugs. For this reason, Drug discovery continues to evolve from a wet lab-based approach to an in silico (i.e., computational) based approach, which takes advantage of the advances made in various fields, such as bacterial genomics, structural bioinformatics, machine learning (ML), and systems biology to enable researchers to rationally design, discover, and develop new antibiotics to combat drug-resistant pathogens. This review aims to provide a comprehensive and critical overview of contemporary in silico antibiotic discovery strategies and their potential to accelerate the development of novel, resistance-resilient, and clinically relevant antimicrobial agents. It examines genome-informed approaches ranging from genomic data generation, resistome analysis, and computational target identification to structure-based drug design, ligand-based and fragment-based discovery, drug repurposing, and the expanding applications of ML and artificial intelligence (AI) in activity prediction, de novo antibiotic design, and resistance evolution modeling. The review also highlights the importance of in silico ADMET prediction in lead optimization and discusses representative case studies demonstrating successful translation of computational predictions into experimental validation. Overall, the integration of digital-first, data-driven, and genome-guided discovery pipelines with experimental validation offers a powerful framework to overcome current challenges in antibiotic development and represents a promising strategy for addressing the global threat of AMR. Lastly, the review was conducted using a structured literature search across major biomedical and computational databases with emphasis on experimentally validated case studies and translational relevance.