Waghu Faiza H, Joseph Shaini, Ghawali Sanket, Martis Elvis A, Madan Taruna, Venkatesh Kareenhalli V, Idicula-Thomas Susan
Biomedical Informatics Centre, ICMR-National Institute for Research in Reproductive Health, Mumbai, India.
Molecular Simulation Group, Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Mumbai, India.
Front Microbiol. 2018 Feb 23;9:325. doi: 10.3389/fmicb.2018.00325. eCollection 2018.
Antimicrobial peptides (AMPs) are gaining attention as substitutes for antibiotics in order to combat the risk posed by multi-drug resistant pathogens. Several research groups are engaged in design of potent anti-infective agents using natural AMPs as templates. In this study, a library of peptides with high sequence similarity to Myeloid Antimicrobial Peptide (MAP) family were screened using popular online prediction algorithms. These peptide variants were designed in a manner to retain the conserved residues within the MAP family. The prediction algorithms were found to effectively classify peptides based on their antimicrobial nature. In order to improve the activity of the identified peptides, molecular dynamics (MD) simulations, using bilayer and micellar systems could be used to design and predict effect of residue substitution on membranes of microbial and mammalian cells. The inference from MD simulation studies well corroborated with the wet-lab observations indicating that MD-guided rational design could lead to discovery of potent AMPs. The effect of the residue substitution on membrane activity was studied in greater detail using killing kinetic analysis. Killing kinetics studies on Gram-positive, negative and human erythrocytes indicated that a single residue change has a drastic effect on the potency of AMPs. An interesting outcome was a switch from monophasic to biphasic death rate constant of due to a single residue mutation in the peptide.
抗菌肽（AMPs）作为抗生素的替代品正受到关注，以应对多重耐药病原体带来的风险。几个研究小组正在以天然抗菌肽为模板设计强效抗感染剂。在本研究中，使用流行的在线预测算法筛选了与髓系抗菌肽（MAP）家族具有高度序列相似性的肽库。这些肽变体的设计方式是保留MAP家族中的保守残基。发现预测算法能够根据肽的抗菌性质有效地对其进行分类。为了提高所鉴定肽的活性，可以使用双层和胶束系统的分子动力学（MD）模拟来设计和预测残基取代对微生物和哺乳动物细胞膜的影响。MD模拟研究的推断与湿实验室观察结果很好地吻合，表明MD指导的合理设计可以导致发现强效抗菌肽。使用杀伤动力学分析更详细地研究了残基取代对膜活性的影响。对革兰氏阳性、阴性和人类红细胞的杀伤动力学研究表明，单个残基变化对抗菌肽的效力有巨大影响。一个有趣的结果是，由于肽中的单个残基突变，死亡率常数从单相转变为双相。
