Zhao Xinghong, Yin Zhongqiong, Breukink Eefjan, Moll Gert N, Kuipers Oscar P
Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.
Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.
Antimicrob Agents Chemother. 2020 May 21;64(6). doi: 10.1128/AAC.02050-19.
Lipid II is an essential precursor for bacterial cell wall biosynthesis and thereby an important target for various antibiotics. Several lanthionine-containing peptide antibiotics target lipid II with lanthionine-stabilized lipid II binding motifs. Here, we used the biosynthesis system of the lantibiotic nisin to synthesize a two-lipid II binding motifs-containing lantibiotic, termed TL19, which contains the N-terminal lipid II binding motif of nisin and the distinct C-terminal lipid II binding motif of one peptide of the two-component haloduracin (i.e., HalA1). Further characterization demonstrated that (i) TL19 exerts 64-fold stronger antimicrobial activity against than nisin(1-22), which has only one lipid II binding site, and (ii) both the N- and C-terminal domains are essential for the potent antimicrobial activity of TL19, as evidenced by mutagenesis of each single and the double domains. These results show the feasibility of a new approach to synthesize potent lantibiotics with two different lipid II binding motifs to treat specific antibiotic-resistant pathogens.
脂磷壁酸质II是细菌细胞壁生物合成的必需前体，因此是各种抗生素的重要作用靶点。几种含羊毛硫氨酸的肽类抗生素通过羊毛硫氨酸稳定的脂磷壁酸质II结合基序靶向脂磷壁酸质II。在此，我们利用乳链菌肽的生物合成系统合成了一种含两个脂磷壁酸质II结合基序的羊毛硫抗生素，称为TL19，它包含乳链菌肽的N端脂磷壁酸质II结合基序和双组分嗜碱菌素（即HalA1）中一个肽段独特的C端脂磷壁酸质II结合基序。进一步的表征表明：（i）TL19对[具体对象未给出]的抗菌活性比仅具有一个脂磷壁酸质II结合位点的乳链菌肽（1-22）强64倍；（ii）N端和C端结构域对TL19的强效抗菌活性均至关重要，对每个单结构域和双结构域进行诱变即可证明这一点。这些结果表明了一种新方法的可行性，即合成具有两种不同脂磷壁酸质II结合基序的强效羊毛硫抗生素来治疗特定的抗生素耐药病原体。
