Leveraging the lipoprotein trafficking pathway for the development of novel antimicrobials

Antimicrobial resistance continues to limit the number of effective antimicrobials to treat bacterial infections. The development of antimicrobials with unique mechanisms of action is crucial to overcoming this threat. By employing various methods of hit identification, such as artificial intelligence, whole-cell screening, and drug repurposing, small-molecules that display activity against bacterial pathogens can be identified. Herein, four molecules (abaucin, enterololin, lolamicin, and fendiline) that were found to have high potency against either Escherichia coli or Acinetobacter baumannii utilizing these drug discovery strategies are described. They were all found to target the lipoprotein trafficking pathway (Lol). Within Gram-negative species, lipoproteins are essential for cell viability, making the Lol pathway an interesting target to exploit for the discovery of antimicrobials. This review highlights the importance of lipoproteins as antibacterial targets and details four examples of the development of small-molecule inhibitors of Lol.