The resistance of biofilms to conventional antibiotics complicates the treatment of chronic cystic fibrosis (CF). We investigated the effects of peptoids, peptides, and conventional antibiotics on the biomass and cell viability within Pseudomonas aeruginosa biofilms. At their MICs, peptoids 1 and 1-C13 4mer caused maximum reductions in biomass and cell viability, respectively. These results suggest that peptoids of this class could be worth exploring for the treatment of pulmonary infections occurring in CF patients.

Tuberculosis is a leading cause of death worldwide. Resistance of Mycobacterium to antibiotics can make treatments less effective in some cases. We tested selected oligopeptoids-previously reported as mimics of natural host defense peptides-for activity against Mycobacterium tuberculosis and assessed their cytotoxicity. A tetrameric, alkylated, cationic peptoid (1-C13 4mer ) was most potent against M. tuberculosis and least cytotoxic, whereas an unalkylated analogue, peptoid 1 4mer , was inactive. Peptoid 1-C13 4mer thus merits further study as a potential antituberculosis drug.

Many organisms rely on antimicrobial peptides (AMPs) as a first line of defense against pathogens. In general, most AMPs are thought to kill bacteria by binding to and disrupting cell membranes. However, certain AMPs instead appear to inhibit biomacromolecule synthesis, while causing less membrane damage. Despite an unclear understanding of mechanism(s), there is considerable interest in mimicking AMPs with stable, synthetic molecules. Antimicrobial N-substituted glycine (peptoid) oligomers (“ampetoids”) are structural, functional and mechanistic analogs of helical, cationic AMPs, which offer broad-spectrum antibacterial activity and better therapeutic potential than peptides. Here, we show through quantitative studies of membrane permeabilization, electron microscopy, and soft X-ray tomography that both AMPs and ampetoids trigger extensive and rapid non-specific aggregation of intracellular biomacromolecules that correlates with microbial death. We present data demonstrating that ampetoids are “fast killers”, which rapidly aggregate bacterial ribosomes in vitro and in vivo. We suggest intracellular biomass flocculation is a key mechanism of killing for cationic, amphipathic AMPs, which may explain why most AMPs require micromolar concentrations for activity, show significant selectivity for killing bacteria over mammalian cells, and finally, why development of resistance to AMPs is less prevalent than developed resistance to conventional antibiotics.

Peptoids are a developing class of peptide-like oligomers originally invented for drug discovery in the early 1990s. While peptides hold great promise for therapeutic applications, current development of peptide-based pharmaceuticals is hindered by their potential for misfolding and aggregation, and particularly, for rapid in vivo degradation post-administration. Researchers have investigated alternative peptide-like constructs that may be able to circumvent such complications. Peptoids comprise a peptide-based backbone and N-substituted glycines for side chain residues, resulting in complete protease-resistance. Synthesis of peptoid sequences up to 50 units in length allows for controlled sequence composition and incorporation of diverse side chain chemistries. Though the landscape of peptoid structure is not clearly defined, secondary, tertiary, loop, turn, and random structures have been identified. As protease-resistant isomers of peptides, peptoids are being developed as versatile molecular tools in biochemistry and biophysics, and are becoming attractive candidates for therapeutic and diagnostic applications. Peptoids have thus far demonstrated bioactivity as protein mimics and as replacements for small molecule drugs. In this review, we discuss the most recent advances in peptoid research on the therapeutic front in the last few years, including in vitro and in vivo studies in the fields of lung surfactant therapy, antimicrobial agents, diagnostics, and cancer. We particularly focus on the biophysical activity of lipid-associated peptoids and their potential therapeutic applications.

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