Host-directed therapeutics against antimicrobial-resistant bacterial infections: emerging roles of multi-omics and systems biology

Abstract

The rapid emergence and global dissemination of antimicrobial resistance (AMR), coupled with the limited development of new antimicrobial agents, have intensified concerns regarding a major global public health crisis. Although antibiotic resistance is primarily driven by microbial mechanisms, host immune and inflammatory responses also play critical roles in determining infection outcomes, pathogen persistence, and treatment efficacy. In this context, host-directed therapies (HDTs) have emerged as a promising complementary strategy by modulating host pathways to enhance antimicrobial immunity, improve bacterial clearance, reduce tissue damage, and restore antibiotic efficacy against multidrug-resistant (MDR) pathogens. Unlike conventional antibiotics, HDTs target conserved host processes, thereby reducing the selective pressure for the emergence of resistance. Recent advances in multi-omics technologies, including genomics, transcriptomics, proteomics, metabolomics, and epigenomics, combined with systems biology approaches, have greatly improved our understanding of host–pathogen interactions during bacterial infections, including those caused by antimicrobial-resistant pathogens. These approaches facilitate the identification of resistance-associated host pathways, molecular networks, and therapeutic targets, while high-throughput screening and computational modelling accelerate the discovery and validation of host-directed interventions. This review highlights emerging host-directed therapeutic strategies against antimicrobial-resistant bacterial infections, with particular emphasis on the use of multi-omics and systems biology to identify and validate host targets associated with resistance phenotypes. We also discuss current approaches to modulate host immune and inflammatory responses, summarize recent advances in host-targeted interventions, and outline the challenges and prospects for translating HDTs into clinical practice to combat AMR.