Nomads UAB, Geležinio vilko 29A, 01112, Vilnius, Lithuania.
Institute of Biotechnology, Vilnius University, Saulėtekio al. 7, 10257, Vilnius, Lithuania.
Sci Rep. 2022 Apr 19;12(1):5865. doi: 10.1038/s41598-022-09865-8.
Rampant rise of multidrug resistant strains among Gram-negative bacteria has necessitated investigation of alternative antimicrobial agents with novel modes of action including antimicrobial proteins such as bacteriocins. The main hurdle in the clinical development of bacteriocin biologics is their narrow specificity and limited strain activity spectrum. Genome mining of bacteria for broadly active bacteriocins have identified a number of promising candidates but attempts to improve these natural multidomain proteins further, for example by combining domains of different origin, have so far met with limited success. We have found that domain swapping of Pseudomonas bacteriocins of porin type, when carried out between phylogenetically related molecules with similar mechanism of activity, allows the generation of highly active molecules with broader spectrum of activity, for example by abolishing strain resistance due to the presence of immunity proteins. The most broadly active chimera engineered in this study, S5-PmnH, exhibits excellent control of Pseudomonas aeruginosa infection in validated murine keratitis and lung infection models.
革兰氏阴性菌中耐药菌株的猖獗出现，促使人们研究具有新型作用模式的替代抗菌药物，包括抗菌蛋白，如细菌素。细菌素生物制剂在临床开发中的主要障碍是其狭窄的特异性和有限的菌株活性谱。对细菌进行广泛活性细菌素的基因组挖掘已经确定了许多有前途的候选者，但迄今为止，试图进一步改进这些天然多结构域蛋白，例如通过组合不同来源的结构域，取得的成功有限。我们发现，当在具有相似作用机制的系统发育上相关的分子之间进行肠孔型假单胞菌细菌素的结构域交换时，可以产生具有更广泛活性谱的高度活性分子，例如通过消除由于存在免疫蛋白而导致的菌株抗性。在这项研究中设计的最广泛活性嵌合体 S5-PmnH，在经过验证的小鼠角膜炎和肺部感染模型中，对铜绿假单胞菌感染具有出色的控制作用。
