New Frontiers for Old Medications: Repurposing Approved Drugs Against Gram-Negative Bacterial Infections.

The global escalation of antimicrobial resistance (AMR) among Gram-negative bacteria poses a severe threat to public health. Traditional antibiotic development struggles to keep pace with emerging resistant strains, necessitating innovative strategies to enhance therapeutic options. This review explores the potential of drug repurposing as a strategic approach to combat Gram-negative bacterial infections, focusing on clinically approved drugs with antibacterial properties or the capacity to enhance antibiotic efficacy through direct or host-directed mechanisms. Within the review, a special section is dedicated to the potential usage of repurposed drugs against bacteria that can be used as biological warfare agents, exposure to which may lead to mass casualties, in particular if these pathogens are resistant to antibiotics. Repurposed drugs exhibit diverse antibacterial mechanisms, including membrane disruption, efflux pump inhibition, iron metabolism interference, quorum sensing suppression, and biofilm inhibition. Additionally, many agents demonstrated host-directed therapeutic effects by modulating inflammatory responses, enhancing autophagy, or boosting innate immune functions. Drug repurposing offers a promising avenue to mitigate the AMR crisis by providing rapid, cost-effective therapeutic solutions. Combining repurposed drugs with existing antibiotics or employing them as host-directed therapies holds significant potential for treating infections caused by multidrug-resistant Gram-negative pathogens. Continued research and clinical validation are essential to translate these findings into effective treatment regimens.