Bacterial Lipoprotein Biosynthetic Pathway as a Potential Target for Structure-based Design of Antibacterial Agents.
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 potential target.


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.
['Xia|Jie|J|', 'Feng|Bo|B|', 'Wen|Gang|G|', 'Xue|Wenjie|W|', 'Ma|Guixing|G|', 'Zhang|Hongmin|H|', 'Wu|Song|S|']
D000900:Anti-Bacterial Agents D001419:Bacteria D001426:Bacterial Proteins D053898:Biosynthetic Pathways D015195:Drug Design D008074:Lipoproteins
bacterial lipoproteins Antibiotic resistance LspA Lgt Lnt benzamides globomycin myxovirescin.