Combinatorial and Host-Directed Therapies Against Intracellular Bacterial Pathogens

Intracellular bacterial pathogens pose a major challenge to current antimicrobial therapies due to their ability to survive and replicate within host cells, where they are partially protected from both immune defenses and antibiotic exposure. This intracellular lifestyle is associated with treatment failure, relapse, and the emergence of antimicrobial resistance, particularly in chronic and persistent infections. Conventional monotherapies often display limited intracellular efficacy as a result of poor cellular penetration, altered bacterial metabolism, and pathogen-driven manipulation of host cellular pathways. In response, combinatorial therapeutic strategies (including antibiotic combinations, host-directed therapies, and drug repurposing approaches) have emerged as promising alternatives to overcome these limitations. By simultaneously targeting bacterial viability, persistence mechanisms, and host factors required for intracellular survival, such approaches offer the potential to enhance intracellular drug activity, reduce resistance development, and improve clinical outcomes in difficult-to-treat bacterial infections.The primary goal of this Research Topic is to address the persistent therapeutic failure associated with intracellular bacterial infections, which remain inadequately controlled by conventional antimicrobial monotherapies. Intracellular pathogens exploit host cellular niches to evade immune clearance, tolerate antibiotic exposure, and enter metabolically altered states that promote persistence and resistance. Current drug development pipelines rarely account for intracellular pharmacokinetics, host-pathogen interactions, or the dynamic nature of bacterial survival within host cells.Specific themes include, but are not limited to: antibiotic–antibiotic and antibiotic–host-targeted combinations; host-directed therapies modulating cellular pathways exploited by intracellular bacteria; drug repurposing and repositioning strategies; pharmacokinetic and pharmacodynamic considerations in intracellular settings; mechanisms of drug synergy and antagonism; redox stress and metabolic interference approaches; and advanced in vitro, ex vivo, and in vivo models for evaluating intracellular antibacterial activity. Studies incorporating systems biology, omics-based analyses, or computational and AI-assisted methods to identify or optimize therapeutic combinations are also encouraged. We welcome Original Research articles, Reviews, Mini-Reviews, Methods, Perspectives, and Brief Research Reports.frontiersin.org/journals/pharmacology/about Topic editors: Michal Letek, Volker Behrends Source: https://www.frontiersin.org/research-topics/77761/combinatorial-and-host-directed-therapies-against-intracellular-bacterial-pathogens