Abstract
Antimicrobial peptides (AMPs) are anti-infectives that have the potential to be used as a novel and untapped class of biotherapeutics. Modes of action of antimicrobial peptides include interaction with the cell envelope (cell wall, outer- and inner-membrane). A comprehensive understanding of the peculiarities of interaction of antimicrobial peptides with the cell envelope is necessary to perform a rational design of new biotherapeutics, against which working out resistance is hard for microbes. In order to enable de novo design with low cost and high throughput, in silico predictive models have to be invoked. To develop an efficient predictive model, a comprehensive understanding of the sequence-to-function relationship is required. This knowledge will allow us to encode amino acid sequences expressively and to adequately choose the accurate AMP classifier. A shared protective layer of microbial cells is the inner, plasmatic membrane. The interaction of AMP with a biological membrane (native and/or artificial) has been comprehensively studied. We provide a review of mechanisms and results of interactions of AMP with the cell membrane, relying on the survey of physicochemical, aggregative, and structural features of AMPs. The potency and mechanism of AMP action are presented in terms of amino acid compositions and distributions of the polar and apolar residues along the chain, that is, in terms of the physicochemical features of peptides such as hydrophobicity, hydrophilicity, and amphiphilicity. The survey of current data highlights topics that should be taken into account to come up with a comprehensive explanation of the mechanisms of action of AMP and to uncover the physicochemical faces of peptides, essential to perform their function. Many different approaches have been used to classify AMPs, including machine learning. The survey of knowledge on sequences, structures, and modes of actions of AMP allows concluding that only possessing comprehensive information on physicochemical features of AMPs enables us to develop accurate classifiers and create effective methods of prediction. Consequently, this knowledge is necessary for the development of design tools for peptide-based antibiotics.
Highlights
Introduction published maps and institutional affilAntimicrobial peptides (AMPs) can play an important role in a novel class of biotherapeutics
AMPs, as membrane-active peptides, possess properties such as amphipathicity and positive charge, the existence of different targets at the plasma membrane and cell wall explains the wide spectrum of physicochemical features expressed by AMP amino acid sequences
When the portion of the Pro in the AMPs is very high, as in the Pro-rich antimicrobial peptides (PrAMPs), the mode of action does not involve the lysis of bacterial membranes but only penetration into susceptible cells, where PrAMPs act on intracellular targets [95]
Summary
Interaction with an envelope, as a rule, begins by binding to the outer layer of the envelope, which can be followed by either inhibition of the vital pathways in the outer layer of the envelope or by passing through it and reaching the plasma membrane. The composition and structure of the cell wall can be a determinant of AMP’s concentration on the lipid bilayer surface as well, and, of the mode of interaction with the plasma membrane [7]. AMP’s physicochemical features and the compositions of the cell wall or outer membrane determine AMP’s concentration on the plasma membrane surface and mode of interaction with the membrane [7]. The subtle balance between physicochemical properties of peptides and compositions of the cell wall and lipid bilayer (outer and/or inner membrane) determines the mode of action of AMP. Studies of the relationships between AMP’s physicochemical properties (PCP), compositions of the cell wall and/or lipid bilayer, and results of interaction with the envelope have uncovered many aspects of the mechanisms of action.
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