Antimicrobial Peptides: Successes, Challenges and Unanswered Questions

Abstract

Multidrug antibiotic resistance is an increasingly serious public health problem worldwide. Thus, there is a significant and urgent need for the development of new classes of antibiotics that do not induce resistance. To develop such antimicrobial compounds, we must look toward agents with novel mechanisms of action. Membrane permeabilizing antimicrobial peptides (AMPs) are good candidates because they act without high specificity toward a protein target, which reduces the likelihood of induced resistance. Understanding the mechanism of membrane permeabilization is crucial for the development of AMPs into useful anti-microbial agents. Various models, some phenomenological and others more quantitative or semi-molecular, have been proposed to explain the action of antimicrobial peptides. While these models explain many aspects of AMP action, none of the models captures all the experimental observations and significant questions remain unanswered. Here we discuss the state of the field and pose some questions that, if answered, could speed the discovery of clinically useful peptide antibiotics.

New trends in peptide-based anti-biofilm strategies: a review of recent achievements and bioinformatic approaches

“…Synthetic AMPs, produced by de novo synthesis or by modification of existing AMPs, emerged as an alternative to reduce production costs (Wimley and Hristova 2011). Recently, some reviews (Vooturi and Firestine 2010;Giuliani and Rinaldi 2011) have reported the engineering of AMP mimetics or peptidomimetics, ie non-peptide molecules aimed at retaining and improving the basic features of AMPs.…”

“…Moreover, compared with conventional antimicrobials, which are generally active only against bacteria or fungi, AMPs exert activity against a broad spectrum of microorganisms, such as both Gram-negative and Gram-positive bacteria, including drug-resistant strains, parasites, enveloped viruses and even some cancer cells (Sang and Blecha 2008;Splith and Neundorf 2011;Wimley and Hristova 2011). AMPs are also cell specific and are able to distinguish host from non-host cells based on their charge (Beckloff et al 2007).…”

“…Most AMPs permeabilize microbial membranes, inducing either a large-scale failure or small defects that dissipate the transmembrane potential, which results in cell death (Sang and Blecha 2008;Wimley and Hristova 2011). This mechanism of action does not depend on the recognition of chiral targets and, (Tomasinsig and Zanetti 2005) .…”

“…Not cytotoxic on mammalian cells (Vooturi and Firestine 2010) therefore, all D-enantiomers are equally active, giving AMPs a broad action spectrum (Podda et al 2006). The mechanisms of action of AMPs are divided into pore and non-pore models (Wimley and Hristova 2011). Pore models account for the formation of membrane-spanning pores, namely the 'barrel stave pore model' (Rapaport and Shai 1991), in which AMPs interact to form a hydrophilic channel, and the 'toroidal pore model' (Ludtke et al 1996), in which AMPs affect the curvature of the membrane.…”

Single-cell, real-time detection of oxidative stress induced in Escherichia coli by the antimicrobial peptide CM15

“…antimicrobial peptide | oxidative stress | CM15 | real-time ROS assay | E. coli I n nature, multicellular organisms produce antimicrobial peptides (AMPs) that participate in the first line of defense against bacterial infection (1). These are ancient molecules that kill a broad, phylogenetically diverse spectrum of bacteria.…”