Non-proteinogenic Amino Acids in Lacticin 481 Analogues Result in More Potent Inhibition of Peptidoglycan Transglycosylation

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• 作者：Patrick J. Knerr ; Trent J. Oman ; Chantal V. Garcia De Gonzalo ; Tania J. Lupoli ; Suzanne Walker ; Wilfred A. van der Donk
• 刊名：ACS Chemical Biology
• 出版年：2012
• 出版时间：November 16, 2012
• 年：2012
• 卷：7
• 期：11
• 页码：1791-1795
• 全文大小：302K
• 年卷期：v.7,no.11(November 16, 2012)
• ISSN：1554-8937

文摘

Lantibiotics are ribosomally synthesized and post-translationally modified peptide natural products that contain the thioether structures lanthionine and methyllanthionine and exert potent antimicrobial activity against Gram-positive bacteria. At present, detailed modes-of-action are only known for a small subset of family members. Lacticin 481, a tricyclic lantibiotic, contains a lipid II binding motif present in related compounds such as mersacidin and nukacin ISK-1. Here, we show that lacticin 481 inhibits PBP1b-catalyzed peptidoglycan formation. Furthermore, we show that changes in potency of analogues of lacticin 481 containing non-proteinogenic amino acids correlate positively with the potency of inhibition of the transglycosylase activity of PBP1b. Thus, lipid II is the likely target of lacticin 481, and use of non-proteinogenic amino acids resulted in stronger inhibition of the target. Additionally, we demonstrate that lacticin 481 does not form pores in the membranes of susceptible bacteria, a common mode-of-action of other lantibiotics.