Advances in Small Molecule Inhibitors Targeting the Bacterial Lipoprotein Transport System (Lol) in Gram-Negative Bacteria.

The escalating threat of antimicrobial resistance (AMR) necessitates the urgent development of novel antibiotics, particularly those against multidrug-resistant gram-negative bacteria. These pathogens possess formidable structural defenses, including an impermeable outer membrane (OM) and robust efflux pumps, which hinder antibiotic efficacy. A promising therapeutic target is the lipoprotein transport system (Lol), which is essential for bacterial viability. The LolABCDE complex ensures the precise localization of lipoproteins, which is crucial for maintaining outer membrane integrity and cell survival. Disruption of this system results in severe structural and functional defects that lead to bacterial cell death. This review explores the recent advances in small-molecule inhibitors targeting the Lol system and examines the mechanisms of LolABCDE function, along with the structural and biochemical characteristics of its components. We also summarize the progress made in the discovery and optimization of inhibitors, including their modes of action, resistance mechanisms, and therapeutic potential. Despite significant progress, challenges, such as limited drug permeability and emerging resistance, continue to hinder therapeutic success. Overcoming these challenges necessitates strategies to enhance inhibitor selectivity and bypass the intrinsic defense mechanisms of gram-negative bacteria. This review aims to provide insights into the potential of targeting the Lol system as a novel strategy for combating antimicrobial resistance and developing effective therapies against gram-negative bacterial infections.