Anticandidal Activity of Omiganan and Its Retro Analog Alone and in Combination with Fluconazole

Abstract

Vulvovaginal candidiasis (VVC) is a vaginal infection that manifests itself as several symptoms which can lead to various life-threatening complications. The majority of VVC is caused by Candida albicans strains, and it is estimated that approximately 75% of women worldwide would suffer from this condition at least once during their lifetime. Surprisingly, the detailed pathomechanism of yeast-like fungi invasions in vagina is not yet fully understood. However, the ability to form biofilm on vaginal mucosa is considered as one of the critical factors associated with failure of the therapy and recurrences of the disease. Antimicrobial peptides (AMPs) are a promising class of compounds that are receiving a growing interest owing to their antibacterial, antifungal, and antibiofilm properties. Omiganan is a synthetic analog of Indolicidin that is characterized by wide spectrum of antimicrobial and antibiofilm activities. Recent reports suggest improved activity of analogs with a reversed sequence (retro-analog concept). Therefore, Omiganan and its retro analog were tested against planktonic forms and biofilm of 18 Candida strains isolated from VVC. Moreover, the synergy between the AMPs and fluconazole was studied as well. The AMPs appeared to be effective against C. albicans biofilm, and the reversion of the sequence generally led to an improved antimicrobial activity. Furthermore, confocal and scanning electron microscopic visualizations revealed the effectiveness of AMPs-fluconazole combinations also against fluconazole-resistant strains. Graphical Abstract

The Antimicrobial Activity of Omiganan Alone and In Combination against Candida Isolated from Vulvovaginal Candidiasis and Bloodstream Infections

“…For this reason, it is necessary to search for alternative methods of treating fungal infections based on antimicotics that effectively eradicate this structure. Antimicrobial peptides (AMPs), including Omiganan, might meet this criterion, as promising activity has already been described [ 38 ]. In the case of VVC, the MIC results obtained in this study show that fluconazole is highly active against planktonic forms of Candida .…”

“…Although, initially, in our previous report for three strains of Candida spp., the FIC determination indicated an antagonism between Omiganan and fluconazole. However, in the course of our studies on a larger group of strains, we found an additive and/or synergistic effect [ 38 ]. In both the vaginal and blood-derived strains, addition was the most common effect, affecting the majority of C. albicans isolates (6/8 with VVC and 5/6 with BSI) and 100% of the strains from the NCAC group.…”

“…It has been observed that under the influence of azoles, there is a change in the fungal cell membrane correlated with the disturbance of its structure and increased permeability to ATP and K + ions, which is directly responsible for the fungistatic effect of this group of compounds [ 2 , 64 , 65 ]. Omiganan, on the contrary, acts directly on the fungal cell membranes, leading to their permeabilization and, as a result, cell death [ 38 ]. It is assumed that Omiganan facilitates the penetration of fluconazole into the cell interior, and thus helps to achieve its molecular target [ 33 , 66 ].…”

“…Omiganan (ILRWPWWPWRRK-NH 2 ) was synthesized as described previously [ 38 ]. The peptide was synthesized manually by the solid-phase method using Fmoc chemistry on polystyrene Rink amide resin with a loading of 1.0 mmol/g (Orpegen Peptide Chemicals GmbH, Heidelberg, Germany).…”

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

“…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 .…”