Institute of Biochemistry, Heinrich-Heine-University Duesseldorf, Universitaetsstrasse 1, 40225 Duesseldorf, Germany.
Institute of Biochemistry, Heinrich-Heine-University Duesseldorf, Universitaetsstrasse 1, 40225 Duesseldorf, Germany.
Bioorg Med Chem. 2019 Sep 1;27(17):3947-3953. doi: 10.1016/j.bmc.2019.07.014. Epub 2019 Jul 10.
The rising existence of antimicrobial resistance, confirms the urgent need for new antimicrobial compounds. Lantibiotics are active in a low nanomolar range and represent good compound candidates. The lantibiotic nisin is well studied, thus it is a perfect origin for exploring novel lantibiotics via mutagenesis studies. However, some human pathogens like Streptococcus agalactiae COH1 already express resistance proteins against lantibiotics like nisin. This study presents three nisin variants with mutations in the hinge-region and determine their influence on both the growth inhibition as well as the pore-forming activity. Furthermore, we analyzed the effect of these mutants on the nisin immunity proteins NisI and NisFEG from Lactococcus lactis, as well as the nisin resistance proteins SaNSR and SaNsrFP from Streptococcus agalactiae COH1. We identified the nisin variant NMKIV with an extended hinge-region, to be an excellent candidate for further studies to eventually overcome the lantibiotic resistance in human pathogens, since these proteins do not recognize this variant well.
抗菌药物耐药性的不断出现，证实了我们急需开发新的抗菌化合物。类细菌素在纳摩尔浓度范围内具有活性，是很好的候选化合物。其中，乳链菌肽的研究较为透彻，因此它是通过突变研究探索新型类细菌素的理想起点。然而，一些人类病原体，如无乳链球菌 COH1，已经表达了针对乳链菌肽等类细菌素的耐药蛋白。本研究提出了三种铰链区突变的乳链菌肽变体，并确定了它们对生长抑制和孔形成活性的影响。此外，我们还分析了这些突变体对来自乳酸乳球菌的乳链菌肽免疫蛋白 NisI 和 NisFEG 以及来自无乳链球菌 COH1 的乳链菌肽耐药蛋白 SaNSR 和 SaNsrFP 的影响。我们发现具有扩展铰链区的 NMKIV 变体是一个很好的候选者，可进一步研究以最终克服人类病原体中的类细菌素耐药性，因为这些蛋白不能很好地识别这种变体。
