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

Abstract

Vulvovaginal candidiasis (VVC) occurs in over 75% of women at least once during their lifetime and is an infection that significantly affects their health. Candida strains resistant to standard azole antifungal therapy and relapses of VVC are more and more common. Hypothetically, biofilm is one of the main reasons of relapses and failure of the therapy. Ultrashort cationic lipopeptides (USCLs) exhibit high antimicrobial activities. Our previous study on USCLs revealed that disulfide cyclization can result in selective antifungal compounds. Therefore, four USCL were selected and their antifungal activity were studied on 62 clinical strains isolated from VVC. The results showed that cyclic analogs have increased selectivity between fungal cells and keratinocytes and improved anticandidal activity than their linear analogs against both planktonic and biofilm cultures. On the other hand, linear lipopeptides in combination with fluconazole showed the synergistic effect. It was found that the minimum inhibitory concentrations of the tested compounds in combination with fluconazole were at least four times lower than when used separately. Our results indicate that combination therapy of VVC with USCLs and fluconazole at low non-toxic concentrations can be beneficial owing to the synergistic effect. However, further in vivo studies are needed to confirm this hypothesis.

Two promising Bacillus-derived antifungal lipopeptide leads AF4 and AF5 and their combined effect with fluconazole on the in vitro Candida glabrata biofilms

“…Two ultrashort cationic cyclic lipopeptides (USCLs), as previously reported (Neubauer et al, 2020), showed antibiofilm activities, wherein the mean biofilm inhibitory concentrations were 87 μg/mL (Neubauer et al, 2020). Very recently, two USCLs were reported with a minimum biofilm eradication concentration of 64 μg/mL against isolates from vulvovaginal candidiasis (Neubauer et al, 2020;Czechowicz et al, 2021). A battery of natural and synthetic peptides has been reported to suppress the biofilm's metabolic activity (Nieminen et al, 2014;Nithyanand et al, 2015).…”

“…Frontiers in Pharmacology frontiersin.org Czechowicz et al, 2021). Appropriate combinations of antifungal agents may be helpful to overcome drug resistance; in this light, exploring the synergistic or additive effect of lipopeptides with other existing antibiotics may hold the future key (Patel et al, 2015).…”