Fighting the invader: strategies against intracellular bacteria

Intracellular pathogenic bacteria are often-overlooked agent of chronic, recurrent and difficult-to-treat infections in a context of escalating antimicrobial resistance. By hiding within professional and non-professional phagocytes, adopting dormant or slow-replicative states and rewiring host pathways, these pathogens successfully evade both immune clearance and conventional antibiotic therapy, thus contributing to treatment failure and, potentially, carcinogenesis. Here we synthesise how obligate and facultative intracellular bacteria invade and persist within host cells, and interpret these processes as interconnected, engineerable modules of the host-pathogen interplay. Using Staphylococcus aureus as a paradigm of facultative intracellular persistence across diverse tissues, we highlight how these pathways generate long-lived intracellular reservoirs that are poorly addressed by current drugs. Building on this framework, we discuss emerging strategies that explicitly apply engineering principles and tools to intracellular infections, including AI-assisted discovery of novel anti-infectives, rational design of host-directed therapies acting on host pathways, microbiota-based interventions, RNA-based approaches, drug repurposing and combinatorial regimens. We argue that integrating pathogen- and host-targeted strategies within a design-build-test-learn cycle, supported by computational modelling and careful attention to safety and pharmacokinetics, offers a route to engineer eradication of intracellular reservoirs, extend antibiotic lifespan and accelerate translation of new therapies against multidrug-resistant infections.