Chen Heng-Li, Su Pei-Yi, Kuo Shu-Chen, Lauderdale Tsai-Ling Y, Shih Chiaho
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan.
Front Microbiol. 2018 Jun 28;9:1440. doi: 10.3389/fmicb.2018.01440. eCollection 2018.
The emergence of antibiotic-resistant bacteria has threatened our health worldwide. There is an urgent need for novel antibiotics. Previously, we identified a novel 37-mer antimicrobial peptide (AMP), HBcARD, with broad spectrum antimicrobial activity. Here, we improved the efficacy of HBcARD, by re-engineering the peptide, including the addition of a new cysteine to its C-terminus (CTC). The new 28-mer derivative, D-150-177C, contains all D-form arginines, in addition to a C-terminal cycteine. This peptide can kill antibiotic-resistant clinical isolates of Gram-negative bacteria, and is more potent than the parental HBcARD peptide in a mouse sepsis model. In another lung infection mouse model, D-150-177C showed protection efficacy against colistin-resistant . Unlike colistin, we observed no acute toxicity of D-150-177C . Interestingly, we found that CTC modification could enhance the antibacterial activity of several other AMPs, such as buforinII and lysin. The potential application and mechanism of this CTC method as a general approach to improving drug efficacy, warrants further investigation in the future.
抗生素耐药细菌的出现已在全球范围内威胁到我们的健康。迫切需要新型抗生素。此前，我们鉴定出一种具有广谱抗菌活性的新型37肽抗菌肽（AMP），即HBcARD。在此，我们通过对该肽进行重新设计来提高HBcARD的功效，包括在其C末端添加一个新的半胱氨酸（CTC）。新的28肽衍生物D-150-177C除了含有一个C末端半胱氨酸外，还全部由D型精氨酸组成。该肽能杀死革兰氏阴性菌的抗生素耐药临床分离株，并且在小鼠脓毒症模型中比亲本HBcARD肽更有效。在另一个肺部感染小鼠模型中，D-150-177C对耐黏菌素菌株显示出保护功效。与黏菌素不同，我们未观察到D-150-177C有急性毒性。有趣的是，我们发现CTC修饰可以增强其他几种抗菌肽的抗菌活性，如蟾蜍灵II和溶菌酶。作为一种提高药物疗效的通用方法，这种CTC方法的潜在应用和机制值得未来进一步研究。
