Background: Antibiotic resistance is currently a serious problem for global public
health. To this end, discovery of new antibacterial drugs that interact with novel targets is important.
The biosynthesis of lipoproteins is vital to bacterial survival and its inhibitors have
shown efficacy against a range of bacteria, thus bacterial lipoprotein biosynthetic pathway is a
Methods: At first, the literature that covered the basic concept of bacterial lipoprotein biosynthetic
pathway as well as biochemical characterization of three key enzymes was reviewed.
Then, the recently resolved crystal structures of the three enzymes were retrieved from Protein
Data Bank (PDB) and the essential residues in the active sites were analyzed. Lastly, all
the available specific inhibitors targeting this pathway and their Structure-activity Relationship
(SAR) were discussed.
Results: We briefly introduce the bacterial lipoprotein biosynthetic pathway and describe the
structures and functions of three key enzymes in detail. In addition, we present much knowledge
on ligand recognition that may facilitate structure-based drug design. Moreover, we focus
on the SAR of LspA inhibitors and discuss their potency and drug-likeness.
Conclusion: This review presents a clear background of lipoprotein biosynthetic pathway and
provides practical clues for structure-based drug design. In particular, the most up-to-date
knowledge on the SAR of lead compounds targeting this pathway would be a good reference
for discovery of a novel class of antibacterial agents.