Protein-Protein Interactions as Promising Molecular Targets for Novel Antimicrobials Aimed at Gram-Negative Bacteria

Antibiotic resistance, especially among Gram-negative bacterial strains, places a massive burden on global healthcare systems as resistance development has outpaced antibiotic discovery. Protein-protein interactions, successful in other therapeutic contexts, are emerging as promising, yet underexplored, targets for the development of novel classes of antibacterials. Pathogen-specific protein-protein interactions are attractive targets because they are often structurally and functionally distinct from host proteins and are less likely to elicit rapid resistance. This review summarizes recent developments in targeting protein-protein interactions in Gram-negative bacteria, focusing on the modulation of five critical cellular processes: membrane regulation, replication, transcription, translation, and toxin-antitoxin systems. We highlight the design and discovery of both small-molecule and peptide-based inhibitors. While many identified modulators exhibit potent in vitro activity against their respective targets, achieving effective penetration of the complex Gram-negative cell envelope remains a major challenge. Nevertheless, the diverse and essential nature of these bacteria-specific protein-protein interactions represents an attractive strategy for developing next-generation antimicrobials to combat drug-resistant pathogens.