pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

Abstract

Antimicrobial peptides (AMPs) are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that utilise pH dependent antimicrobial mechanisms, and here we review research into this area. This review shows that these antimicrobial molecules are produced by a diverse spectrum of creatures, including vertebrates and invertebrates, and are primarily cationic, although a number of anionic examples are known. Some of these molecules exhibit high pH optima for their antimicrobial activity but in most cases, these AMPs show activity against microbes that present low pH optima, which reflects the acidic pH generally found at their sites of action, particularly the skin. The modes of action used by these molecules are based on a number of major structure/function relationships, which include metal ion binding, changes to net charge and conformational plasticity, and primarily involve the protonation of histidine, aspartic acid and glutamic acid residues at low pH. The pH dependent activity of pore forming antimicrobial proteins involves mechanisms that generally differ fundamentally to those used by pH dependent AMPs, which can be described by the carpet, toroidal pore and barrel-stave pore models of membrane interaction. A number of pH dependent AMPs and antimicrobial proteins have been developed for medical purposes and have successfully completed clinical trials, including kappacins, LL-37, histatins and lactoferrin, along with a number of their derivatives. Major examples of the therapeutic application of these antimicrobial molecules include wound healing as well as the treatment of multiple cancers and infections due to viruses, bacteria and fungi. In general, these applications involve topical administration, such as the use of mouth washes, cream formulations and hydrogel delivery systems. Nonetheless, many pH dependent AMPs and antimicrobial proteins have yet to be fully characterized and these molecules, as a whole, represent an untapped source of novel biologically active agents that could aid fulfillment of the urgent need for alternatives to conventional antibiotics, helping to avert a return to the pre-antibiotic era.

Resistin-like molecule β is a bactericidal protein that promotes spatial segregation of the microbiota and the colonic epithelium

“…S3 B and C). This is consistent with the salt and pH sensitivity of other antimicrobial peptides (21) and likely reflects the fact that such antibacterial proteins have evolved to function in the acidic, low-salt environment that is present in the mucus layer (22). The requirement for these specialized conditions might also explain why RELMβ was previously reported to lack antibacterial activity (12).…”

pH in nature, humans and skin

“…Fungi are able to grow in a wide range of pH values . In addition to the direct effect of the acidity, pH regulates the activity of antimicrobial peptides …”

Antimicrobial and Antibiofilm Peptides

“…However, in the 1960s, due to the increase in the number of multidrug-resistant microbial pathogens, the attention of the scientific community turned to the study of antimicrobial peptides [4][5][6][7]. Antimicrobial peptides are small molecules (10-100 amino acids) produced by all living organisms that play an essential role in the innate immunity [8,9]. Since the discovery of the first groups of AMPs, the magainins from the skin of the African clawed frog Xenopus laevis by Zasloff et al [10][11][12] and the first antimicrobial peptides A further aspect of the AMPs activity that has been much investigated in recent years and needs to be more deeply considered is their ability to affect biofilm formation.…”