Insights into the Mechanism of Action of the Two-Peptide Lantibiotic Lacticin 3147

被引:43
作者
Bakhtiary, Alireza [1 ]
Cochrane, Stephen A. [2 ]
Mercier, Pascal [3 ]
McKay, Ryan T. [1 ]
Miskolzie, Mark [1 ]
Sit, Clarissa S. [4 ]
Vederas, John C. [1 ]
机构
[1] Univ Alberta, Dept Chem, Edmonton, AB T6G 2G2, Canada
[2] Queens Univ Belfast, Sch Chem & Chem Engn, Belfast BT9 5AG, Antrim, North Ireland
[3] Univ Alberta, Natl High Field NMR Ctr, Edmonton, AB T6G 2E1, Canada
[4] St Marys Univ, Dept Chem, Halifax, NS B3H 3C3, Canada
基金
英国惠康基金; 加拿大自然科学与工程研究理事会;
关键词
LIPID II-BINDING; GRAM-NEGATIVE BACTERIA; LACTOCOCCUS-LACTIS; MERSACIDIN; NISIN; BIOSYNTHESIS; DISCOVERY; PEPTIDES; IDENTIFICATION; HALODURACIN;
D O I
10.1021/jacs.7b04728
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Lacticin 3147 is a two peptide lantibiotc (LtnA1 and LtnA2) that displays nanomolar activity against many Gram-positive bacteria. Lacticin 3147 may exert its antimicrobial effect by several mechanisms. Isothermal titration calorimetry experiments show that only LtnA1 binds to the peptidoglycan precursor lipid II, which could inhibit peptidoglycan biosynthesis. An experimentally supported model of the resulting complex suggests that the key binding partners are the C-terminus of LtnA1 and pyrophosphate of lipid II. A combination of in vivo and in vitro assays indicates that LtnA1 and LtnA2 can induce rapid membrane lysis without the need for lipid II binding. However, the presence of lipid II substantially increases the activity of lacticin 3147. Furthermore, studies with synthetic LtnA2 analogues containing either desmethyl- or oxa-lanthionine rings confirm that the precise geometry of these rings is essential for this synergistic activity.
引用
收藏
页码:17803 / 17810
页数:8
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