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

[ Vol. 27 , Issue. 7 ]

Author(s):

Jie Xia*, Bo Feng, Gang Wen, Wenjie Xue, Guixing Ma, Hongmin Zhang and Song Wu*   Pages 1132 - 1150 ( 19 )

Abstract:


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.

Keywords:

Antibiotic resistance, bacterial lipoproteins, Lgt, LspA, Lnt, globomycin, myxovirescin, benzamides.

Affiliation:

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, Department of Biology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment and SUSTech-HKU joint laboratories for matrix biology, Southern University of Science and Technology, Shenzhen 518055, Department of Biology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment and SUSTech-HKU joint laboratories for matrix biology, Southern University of Science and Technology, Shenzhen 518055, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050



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