School of Microbiology, University College Cork, Cork, Ireland.
APC Microbiome Ireland, University College Cork, Cork, Ireland.
Mol Microbiol. 2019 Mar;111(3):717-731. doi: 10.1111/mmi.14183. Epub 2019 Feb 12.
The emergence and dissemination of antibiotic resistant bacteria is a major medical challenge. Lantibiotics are highly modified bacterially produced antimicrobial peptides that have attracted considerable interest as alternatives or adjuncts to existing antibiotics. Nisin, the most widely studied and commercially exploited lantibiotic, exhibits high efficacy against many pathogens. However, some clinically relevant bacteria express highly specific membrane-associated nisin resistance proteins. One notable example is the nisin resistance protein that acts by cleaving the peptide bond between ring E and the adjacent serine 29, resulting in a truncated peptide with significantly less activity. We utilised a complete bank of bioengineered nisin (nisin A) producers in which the serine 29 residue has been replaced with every alternative amino acid. The nisin A S29P derivative was found to be as active as nisin A against a variety of bacterial targets but, crucially, exhibited a 20-fold increase in specific activity against a strain expressing the nisin resistance protein. Another derivative, nisin PV, exhibited similar properties but was much less prone to oxidation. This version of nisin with enhanced resistance to specific resistance mechanisms could prove useful in the fight against antibiotic resistant pathogens.
抗生素耐药菌的出现和传播是一个主要的医学挑战。类细菌素是高度修饰的细菌产生的抗菌肽，作为现有抗生素的替代品或辅助物引起了相当大的关注。乳链菌肽是研究和商业开发最广泛的类细菌素，对许多病原体表现出很高的功效。然而，一些与临床相关的细菌表达高度特异性的膜相关乳链菌肽抗性蛋白。一个值得注意的例子是乳链菌肽抗性蛋白，它通过切割环 E 与相邻丝氨酸 29 之间的肽键起作用，导致活性显著降低的截短肽。我们利用了一个完整的工程化乳链菌肽（乳链菌肽 A）生产菌库，其中丝氨酸 29 残基被每种替代氨基酸取代。发现乳链菌肽 A S29P 衍生物对各种细菌靶标与乳链菌肽 A 一样有效，但至关重要的是，对表达乳链菌肽抗性蛋白的菌株的特异性活性提高了 20 倍。另一种衍生物，乳链菌肽 PV，表现出类似的特性，但不易氧化。这种具有增强对特定抗性机制抗性的乳链菌肽版本可能对抗生素耐药病原体的斗争有用。
