Author:
Klubthawee Natthaporn,Adisakwattana Poom,Hanpithakpong Warunee,Somsri Sangdao,Aunpad Ratchaneewan
Abstract
AbstractAntimicrobial peptides (AMPs) are promising alternatives to classical antibiotics for the treatment of drug-resistant infections. Due to their versatility and unlimited sequence space, AMPs can be rationally designed by modulating physicochemical determinants to favor desired biological parameters and turned into novel therapeutics. In this study, we utilized key structural and physicochemical parameters, in combination with rational engineering, to design novel short α-helical hybrid peptides inspired by the well-known natural peptides, cathelicidin and aurein. By comparing homologous sequences and abstracting the conserved residue type, sequence templates of cathelicidin (P0) and aurein (A0) were obtained. Two peptide derivatives, P7 and A3, were generated by amino acid substitution based on their residue composition and distribution. In order to enhance antimicrobial activity, a hybrid analog of P7A3 was designed. The results demonstrated that P7A3 had higher antibacterial activity than the parental peptides with unexpectedly high hemolytic activity. Strikingly, C-terminal truncation of hybrid peptides containing only the α-helical segment (PA-18) and shorter derivatives confer potent antimicrobial activity with reduced hemolytic activity in a length‐dependent manner. Among all, PA-13, showed remarkable broad-spectrum antibacterial activity, especially against Pseudomonas aeruginosa with no toxicity. PA-13 maintained antimicrobial activity in the presence of physiological salts and displayed rapid binding and penetration activity which resulted in membrane depolarization and permeabilization. Moreover, PA-13 showed an anti-inflammatory response via lipopolysaccharide (LPS) neutralization with dose-dependent, inhibiting, LPS-mediated Toll-like receptor activation. This study revealed the therapeutic potency of a novel hybrid peptide, and supports the use of rational design in development of new antibacterial agents.
Publisher
Springer Science and Business Media LLC
Reference54 articles.
1. Rossolini, G. M., Arena, F., Pecile, P. & Pollini, S. Update on the antibiotic resistance crisis. Curr Opin Pharmacol 18, 56–60, https://doi.org/10.1016/j.coph.2014.09.006 (2014).
2. World Health Organization. Antimicrobial Resistance: Global Report on Surveillance 2014. (2014) Available at, http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf (Date of access: 24/02/2018).
3. Zhang, L. J. & Gallo, R. L. Antimicrobial peptides. Curr Biol 26, R14–19, https://doi.org/10.1016/j.cub.2015.11.017 (2016).
4. Huang, Y., Huang, J. & Chen, Y. Alpha-helical cationic antimicrobial peptides: relationships of structure and function. Protein Cell 1, 143–152, https://doi.org/10.1007/s13238-010-0004-3 (2010).
5. Waghu, F. H. et al. Designing Antibacterial Peptides with Enhanced Killing Kinetics. Front Microbiol 9, 325, https://doi.org/10.3389/fmicb.2018.00325 (2018).
Cited by
68 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献