Nylon-3 Polymers with Selective Antifungal Activity

Most antimicrobial peptides act upon target microorganisms by permeabilizing their membranes. The mode of action is often assessed by vesicle leakage experiments that use model membranes, with the assumption that biological activity arises from permeabilization of the lipid bilayer. The current work aims to extend the interpretation of vesicle leakage results and examine the correlation between vesicle leakage and antimicrobial activity. To this end, we used a lifetime-based leakage assay with calcein-loaded vesicles to study the membrane permeabilizing properties of a novel antifungal polymer poly-NM, two of its analogs, and a series of detergents. In conjunction, the biological activities of these compounds against Candida albicans were assessed and correlated with data from vesicle leakage. Poly-NM induces all-or-none leakage in polar yeast lipid vesicles at the polymer’s MIC, 3 μg/mL. At this and higher concentrations, complete leakage after an initial lag time was observed. Concerted activity tests imply that this polymer acts independently of the detergent octyl glucoside (OG) for both vesicle leakage and activity against C. albicans spheroplasts. In addition, Poly-NM was found to have negligible activity against zwitterionic vesicles and red blood cells. Our results provide a consistent, detailed picture of the mode of action of Poly-NM: this polymer induces membrane leakage by electrostatic lipid clustering. In contrast, Poly-MM:CO, a nylon-3 polymer comprised of both cationic and hydrophobic segments, seems to act by a different mechanism that involves membrane asymmetry stress. Vesicle leakage for this polymer is transient (limited to <100%) and graded, non-specific among zwitterionic and polar yeast lipid vesicles, additive with detergent action, and correlates poorly with biological activity. Based on these results, we conclude that comprehensive leakage experiments can provide a detailed description of the mode of action of membrane permeabilizing compounds. Without this thorough approach, it would have been logical to assume that the two nylon-3 polymers we examined act via similar mechanisms; it is surprising that their mechanisms are so distinct. Some, but not all mechanisms of vesicle permeabilization allow for antimicrobial activity.

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“…43 in Tab. 1) had revealed a considerable activity of poly-NM against C. albicans , with a MIC of 3.1 μg/mL.…”

Section: Resultsmentioning

confidence: 99%

Correlating antimicrobial activity and model membrane leakage induced by nylon-3 polymers and detergents

et al. 2015

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“…[65][66][67][68] By varying the specific structures of cationic groups and hydrophobic groups, the antimicrobial activity against particular microbes can be selectively enhanced as well. [69][70][71][72][73][74][75][76][77] It should be noted that the physical chemistry behind the globally amphiphilic antimicrobial cationic polymers needs to be studied furthermore for providing the guidelines for fabrication of antimicrobial materials with tailor-made structures and functions.…”

Section: Antimicrobial Polymers Y Yang Et Almentioning

confidence: 99%

Antimicrobial cationic polymers: from structural design to functional control

Yang

Cai

Huang

et al. 2017

Polym J

212

174

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Antimicrobial cationic polymers mainly contain two functional components: the cationic groups and the hydrophobic groups. The antimicrobial activity is influenced by the type, amount, location and distribution of these two components. This review summarizes the designs and syntheses of antimicrobial cationic polymers by controlling the above two factors. It involves the structural designs from primary to secondary structures, from covalent to noncovalent syntheses and from bulk to surface. Furthermore, it will discuss how to advance structural designs toward functional controls for optimizing the antimicrobial performances and biocompatibility of antimicrobial cationic polymers. It is anticipated that this review will provide some guidelines for developing molecular engineering of antimicrobial cationic polymers with tailor-made structures and functions.

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“…Achieving similar activities against fungi compared to bacteria is somewhat difficult due to the similarities in fungal and mammalian cells, as both are eukaryotes. However, Gellman, Masters and coworkers found out that a group of nylon-3 copolymers (Table 1C) were highly active against Candida albicans while maintaining low hemolytic activity [69]. These sequence-random poly(b-peptide)s are structurally very similar to AMPs since they contain protein like polymer backbone.…”

Section: Random Copolymersmentioning

confidence: 99%