Non-Proteinogenic Amino Acids in Lacticin 481 Analogues Result in More Potent Inhibition of Peptidoglycan Transglycosylation
Knerr, Patrick J.
Oman, Trent J.
Garcia De Gonzalo, Chantal V.
van der Donk, Wilfred A.
Lupoli, Tania J.
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CitationKnerr, Patrick J., Trent J. Oman, Chantal V. Garcia De Gonzalo, Tania J. Lupoli, Suzanne Walker, and Wilfred A. van der Donk. 2012. Non-proteinogenic amino acids in lacticin 481 analogues result in more potent inhibition of peptidoglycan transglycosylation. ACS Chemical Biology 7(11): 1791-1795.
AbstractLantibiotics 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.
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