Structural design of microbicidal cationic oligomers and their synergistic interaction with azoles against Candida albicans

Abstract

Membrane-disrupting synthetic antimicrobial polymers have been well developed as antimicrobial peptide (AMP) mimics to mitigate antimicrobial resistance (AMR). However, synthetic polymers possess inherent drawbacks, being a mixture of different chain lengths, which restricts their clinical applications. In fact, synthetic oligomers with defined chain length and molecular structure could be better representatives of AMPs. Herein, a series of novel imidazolium-ammonium oligomers developed in this work exhibit excellent broad spectrum antimicrobial activity, specifically the salient structure dependent high efficiency against C . albicans . Moreover, synergistic effect emerged when the combined azoles and synthetic oligomers were applied against C . albicans . The detail structural coupling between azoles and oligomers was scrutinized through molecular dynamics simulations to unravel the interaction details with the atomistic resolution. The labile interaction between oligomer and azoles facilitated the transfer of drug into fungal cells, which can be a synergistic solution to prevent the development of resistance on C . albicans .

Antifungal Activity of Linear and Disulfide-Cyclized Ultrashort Cationic Lipopeptides Alone and in Combination with Fluconazole against Vulvovaginal Candida spp.

“…The use of compounds with different mechanisms of action is generally recommended. Combined antifungal therapy has many potential benefits, such as enhancement of the fungicidal effect and broadening the spectrum of activity, which enable to fight polymicrobial infections, reduce the dose of the compounds, and thus also reduce dose-dependent toxicity as well as overcome the resistance of microorganisms [55,56]. It is noted that antimicrobial peptides interacting with the membrane bilayers could, in a way, sensitize Candida cells to fluconazole by increasing azole penetration into the cell, where its molecular target-14α-lanosterol demethylase (Erg enzyme)-is located and involved in ergosterol synthesis.…”

“…In effect, the composition of the cell membrane changes; it liquefies and increases the permeability for K + and ATP, causing a fungistatic effect [57]. On the other hand, the interaction of fluconazole with the cell membrane may enhance its permeabilization by various AMPs, including lipopeptides, and enhance their fungicidal activity [55,58,59]. Other mechanisms that may be responsible for the synergistic effect of combining triazoles with compounds with a different mechanism of action include sequential inhibition of different stages in the mutual biochemical pathway or simultaneous interaction with the Candida cell wall and/or membrane [55].…”

“…Although the mechanisms responsible for this phenomenon remain unexplained, attention is drawn to the beneficial effects of cationic compounds, such as LF, which may enhance the hydrophobicity of the surface of microbial cells and potentiate the antifungal activity of other compounds [61]. Another example is the advantageous synergistic effect of combinations with fluconazole of such positively charged compounds as microbicidal cationic oligomers, styrylpyridinium compounds, and novel antimicrobial peptides such as KABT-AMP derivatives or ToAP2 [55,59,64,65]. Recently, the synergism of fluconazole with surfactin (SU) against C. albicans has been described in more detail.…”

Antifungal Activity of Linear and Disulfide-Cyclized Ultrashort Cationic Lipopeptides Alone and in Combination with Fluconazole Against Vulvovaginal Candida spp.

“…The use of compounds with different mechanisms of action is generally recommended. Combined antifungal therapy has many potential bene ts, such as enhancement of the fungicidal effect and broadening the spectrum of activity, which enable to ght polymicrobial infections, reduce the dose of the compounds, and thus also reduce dose-dependent toxicity as well as overcome the resistance of microorganisms 51,52 . It is noted that antimicrobial peptides interacting with the membrane bilayers could, in a way, sensitize Candida cells to uconazole by increasing azole penetration into the cell, where its molecular target -14α-lanosterol demethylase (Erg enzyme)-is located, involved in ergosterol synthesis.…”

“…In effect, the composition of the cell membrane changes; it lique es and increases the permeability for K + and ATP causing a fungistatic effect 53 . On the other hand, the interaction of uconazole with the cell membrane may enhance its permeabilization by various AMPs, including lipopeptides, and enhance their fungicidal activity 51,54,55 . Other mechanisms that may be responsible for the synergistic effect of combining triazoles with compounds with a different mechanism of action include sequential inhibition of different stages in the mutual biochemical pathway or simultaneous interaction with the Candida cell wall and/or membrane 51 .…”