Synergistic effect of nikkomycin Z with caspofungin and micafungin against Candida albicans and Candida parapsilosis biofilms

Abstract

Antifungal lock therapy has received significant interest in the last few years because the frequently usage of intravascular devices is associated with an increasing number of catheter‐related bloodstream infections caused by Candida species. Antifungal combinations with synergistic interaction can be a good choice for antifungal lock therapy; therefore, interactions were examined between two echinocandins (caspofungin and micafungin) and the chitin synthesis inhibitor nikkomycin Z against Candida albicans and C. parapsilosis biofilms. Susceptibility was evaluated using the XTT‐based checkerboard microdilution method, while the nature of interactions was assessed by calculating fractional inhibitory concentration indices and using the Bliss independence model. Mathematic‐based evaluations were supplemented with fluorescent LIVE/DEAD viability assay. The results obtained by statistical interaction analyses correlated well with the viability assay. The tested echinocandins with nikkomycin Z caused an extended cell death and the structure of the biofilm was sparse compared to the control, especially for C. albicans. The findings support the simultaneous usage of nikkomycin Z and caspofungin or micafungin in alternative therapies such as the antifungal lock therapy. Significance and Impact of the Study Antifungal lock therapy can be a potential therapeutic approach to eradicate the intraluminal Candida biofilms; however, there is no approved lock strategy against fungal species so far. The results of this study provide valuable evidence that nikkomycin Z acts synergistically in combination with caspofungin or micafungin against biofilms. In addition, this synergy was more pronounced for micafungin combined with nikkomycin Z. Therefore, nikkomycin Z can be considered as a potential agent in antifungal lock therapy especially with micafungin against C. albicans or C. parapsilosis biofilms.

Antimicrobial Peptides: a New Frontier in Antifungal Therapy

“…Similar results were obtained for the melanized fungus Alternaria infectoria, involved in opportunistic human infections and respiratory allergies (151). Nikkomycin Z also synergizes with caspofungin or micafungin against Candida biofilms, in particular, C. albicans and C. parapsilosis (152)(153)(154). In fact, the response to caspofungin involves a compensatory increase in chitin synthesis (155)(156)(157), and so the ability of nikkomycin Z to target chitin synthesis is a plausible mechanism to explain the synergy between these two drugs (155).…”

Candida albicans Antifungal Resistance and Tolerance in Bloodstream Infections: The Triad Yeast-Host-Antifungal

“…This synergistic effect was also observed in Alternaria infectoria [169]. In the case of C. albicans biofilm, the combination of echinocandins with nikkomycin Z demonstrated to be synergic, causing an extended cells death [170,171].…”

Pathogenesis and Clinical Relevance of Candida Biofilms in Vulvovaginal Candidiasis

“…Nikkomycin Z has been shown to act synergistically in association with caspofungin or micafungin against biofilms (Kovács et al, 2019).…”

“…Fosso et al, 2018 Cerium nitrate, a member of the lanthanide family Active against planktonic and sessile Candida spp. cells It is able to prevent biofilm formation by C. albicans and C. parapsilosis both in vitro and in vivo Application in medical devices Silva-Dias et al, 2015 Fluconazole analogs with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents These compounds are active against some of the C. albicans and non-albicans Candida strains and are highly effective against clinical strains of C. glabrata and C. parapsilosis Micafungin + ethanol Capsofungin/posaconazole, or amphotericin B, or anidulafungin, or Caspofungin/micafungin in combination with nikkomycin Z Antifungal lock therapy is used to inhibit the formation of the biofilm Walraven and Lee, 2013Basas et al, 2019Kovács et al, 2019 27 new FLC derivatives Broad-spectrum antifungal activity. All compounds inhibit the sterol 14α-demethylase enzyme involved in ergosterol biosynthesis Shrestha et al, 2017 Fluoroquinolones and antifungal agents (from amphotericin B or caspofungin) or rifampicin Chloramphenicol Very useful in immunosuppressed patients Stergiopoulou et al, 2009Vogel et al, 2008 Not valid for use against C. albicans or C. glabrata Antifungal activity comparable to caspofungin and ketoconazole Joseph et al, 2015 Tyrosol and farnesol Strong biofilm inhibition Inhibit the formation of hyphae Monteiro et al, 2017Mehmood et al, 2019 Amphotericin B plus silver hybrid nanoparticles Powerful antifungal activity although the toxicity of the nanoparticles depends on the size, concentration, and pH of the medium and the exposure time to pathogens Leonhard et al, 2018 Amphotericin B plus acetylsalicylic/ibuprofen/ambroxol They are inexpensive, but they increase the risk of bleeding and hyperkalaemia Zhou et al, 2012Sharma et al, 2015Li et al, 2017 KSL-W and SM21 peptides Inhibit biofilm formation by Candida spp.…”