Hazam Prakash Kishore, Phukan Chimanjita, Akhil R, Singh Anjali, Ramakrishnan Vibin
Molecular Informatics and Design Laboratory, Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Guwahati, Assam, 781125, India.
Sci Rep. 2021 Jan 19;11(1):1823. doi: 10.1038/s41598-021-81394-2.
We present design and antibacterial studies of stereochemically diversified antimicrobial peptides against multidrug-resistant bacterial pathogens. Syndiotactic polypeptides are polymers of alternating L and D amino acids with LDLD or DLDL backbone stereochemical sequence, which can form stable gramicidin like helical conformations. We designed, synthesized and characterized eight model molecular systems with varied electrostatic fingerprints, modulated through calibrated sequence positioning. Six out of eight model systems showed very impressive antimicrobial activity against three difficult to treat bacterial species, Gentamicin resistant MRSA, E. coli and Mycobacterium. More importantly, the designed LDLD peptides were equally potent in serum, an important drawback of poly L peptide sequences due to enzyme mediated degradation and ion sensitivity. Further, we tested the activity of the designed peptides against drug-resistant clinical isolates of Staphylococcus aureus and Escherichia coli. Molecular dynamics simulation studies suggest formation of an assembly of individual peptides, preceding the membrane interaction and deformation. The activity estimates are comparable with the available peptide based antimicrobials, and are also highly specific and less toxic as per standard estimates. Incorporation of D amino-acids can significantly expand the peptide design space, which can in turn manifest in future biomaterial designs, especially antimicrobials.
我们展示了针对多重耐药细菌病原体的立体化学多样化抗菌肽的设计及抗菌研究。间同立构多肽是具有LDLD或DLDL主链立体化学序列的L型和D型氨基酸交替的聚合物，可形成稳定的类似短杆菌肽的螺旋构象。我们设计、合成并表征了八个具有不同静电指纹的模型分子系统，通过校准序列定位进行调控。八个模型系统中的六个对三种难以治疗的细菌物种，即庆大霉素耐药的耐甲氧西林金黄色葡萄球菌、大肠杆菌和分枝杆菌，表现出非常令人印象深刻的抗菌活性。更重要的是，所设计的LDLD肽在血清中同样有效，这是聚L肽序列由于酶介导的降解和离子敏感性而存在的一个重要缺陷。此外，我们测试了所设计的肽对金黄色葡萄球菌和大肠杆菌耐药临床分离株的活性。分子动力学模拟研究表明，在膜相互作用和变形之前，单个肽会形成聚集体。活性评估结果与现有的基于肽的抗菌剂相当，并且根据标准评估也具有高度特异性且毒性较小。引入D型氨基酸可以显著扩展肽的设计空间，这反过来可能会在未来的生物材料设计中体现出来，尤其是抗菌材料。
