Abstract
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 Staphylococcus aureus due to a single residue mutation in the peptide.
Highlights
Antimicrobial peptides (AMPs) are diverse, biologically active molecules of the innate immune system
This study demonstrates that prediction algorithms along with molecular dynamics (MD) simulations can be exploited for design of novel AMPs
Helical content is known to influence membrane activity and Circular Dichroism (CD) studies revealed that P1m exhibited higher helical content as compared to P1 (Figure 3)
Summary
Antimicrobial peptides (AMPs) are diverse, biologically active molecules of the innate immune system. AMPs have multiple cellular targets (Lohner, 2017) and this makes it difficult for microbes to develop resistance against them as compared to antibiotics which mostly have a single target. They exert several immunomodulatory properties such as modulation of cytokine and chemokine expression, leukocyte activation (Sorensen et al, 2008) etc. Studies have shown that dysregulation of the generation of AMPs in innate immune responses results in increased susceptibility to microbial infections (Ganz, 2003; Porto et al, 2016; Modi et al, 2017). AMPs play a role in other biological processes such as angiogenesis and wound healing (Veldhuizen et al, 2014)
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