Cationic Amphiphiles, a New Generation of Antimicrobials Inspired by the Natural Antimicrobial Peptide Scaffold

Abstract

2Naturally occurring cationic antimicrobial peptides (AMPs) and their mimics form a diverse class of antibacterial agents currently validated in preclinical and clinical settings for the treatment of infections caused by antimicrobial-resistant bacteria. Numerous studies with linear, cyclic, and diastereomeric AMPs have strongly supported the hypothesis that their physicochemical properties, rather than any specific amino acid sequence, are responsible for their microbiological activities. It is generally believed that the amphiphilic topology is essential for insertion into and disruption of the cytoplasmic membrane. In particular, the ability to rapidly kill bacteria and the relative difficulty with which bacteria develop resistance make AMPs and their mimics attractive targets for drug development. However, the therapeutic use of naturally occurring AMPs is hampered by the high manufacturing costs, poor pharmacokinetic properties, and low bacteriological efficacy in animal models. In order to overcome these problems, a variety of novel and structurally diverse cationic amphiphiles that mimic the amphiphilic topology of AMPs have recently appeared. Many of these compounds exhibit superior pharmacokinetic properties and reduced in vitro toxicity while retaining potent antibacterial activity against resistant and nonresistant bacteria. In summary, cationic amphiphiles promise to provide a new and rich source of diverse antibacterial lead structures in the years to come.The rise in antibiotic resistance among pathogenic bacteria and the declining rate of novel drug discovery are common concerns in medicine (66), driving research into new antibacterial classes and novel drugs in order to maintain the existing ability to treat infectious diseases, especially those caused by multidrug-resistant (MDR) organisms (49, 51).While the enzymatic inhibitors from which many of our strongest antibiotics are derived are highly effective in the microbial world, higher-order organisms do not appear to rely entirely on such selective inhibitors (27). These organisms instead produce a number of broad-range antimicrobial peptides (AMPs), which do not target any single molecule or process but instead associate with cellular membranes, resulting in depolarization, lysis, and cell death through a disruption of the membrane topology. A subset of these peptides is able to translocate into the cell and disrupt cellular processes, such as protein and DNA synthesis (33). AMPs play a key role in the human immune system, and mutations affecting their production and expression have been linked to diseases such as morbus Kostmann and Crohn's disease (56, 75).Membrane targeting offers advantages over standard methods of drug design and antibiotic activity due to the wide variety of active structures and a reduced development of resistance mechanisms (78). Nevertheless, potential cytotoxicity to the host cells remains a major unsolved challenge (43). Mutants resistant to AMPs have been developed in the laboratory (54); however, such mutants may ...

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“…In general, compounds that act by disrupting the prokaryotic cell membrane make the bacteria more vulnerable: disruption of the cell membrane tempers bacterial cell-cell communication essential for collective stressresponse strategies and collective development of drug resistance (6). Cationic amphipathic peptides are very effective antibacterial membrane agents because they target the general properties of the lipid bilayer of the bacterial membrane and cause limited damage to the eukaryotic plasma membrane.…”

Antibacterial activity of amphiphilic tobramycin

“…1 PAs can be divided into amphiphilic and non-amphiphilic PAs. Amphiphilic PAs are comprised of the naturally occurring cationic antimicrobial peptides, synthetic mimics of antimicrobial peptides, polycationic lipopeptides, lipids and surfactants, whereas non-amphiphilic PAs are represented by aminoglycoside antibiotics.…”

Cell-Cell Membrane Fusion Induced by p15 Fusion-associated Small Transmembrane (FAST) Protein Requires a Novel Fusion Peptide Motif Containing a Myristoylated Polyproline Type II Helix

“…4). Two-step models for peptide interactions with membranes are not uncommon, as occurs with amphipathic cationic antimicrobial peptides that use electrostatic interactions to promote initial peptide-membrane interaction followed by membrane lysis or pore formation (55). Lipid anchors have also been used in contrived peptide systems to promote liposome aggregation and membrane fusion (47,56,57), although the fatty acid did not exert these enhancing effects by promoting peptide-liposome binding as occurs with the p15 ectodomain.…”