Antifungal Effect of Novel 2-Bromo-2-Chloro-2-(4-Chlorophenylsulfonyl)-1-Phenylethanone against Candida Strains.

Monika Staniszewska,Magdalena Wieczorek,Héctor M Mora-Montes,Małgorzata Bondaryk,Zbigniew Ochal,Eine Estrada-Mata

doi:10.3389/fmicb.2016.01309

Abstract

We investigated the antifungal activity of novel a 2-bromo-2-chloro-2-(4-chlorophenylsulfonyl)-1-phenylethanone (compound 4). The synthesis of compound 4 was commenced from sodium 4-chlorobenzene sulfinate and the final product was obtained by treatment of α-chloro-β-keto-sulfone with sodium hypobromite. The sensitivity of 63 clinical isolates belonging to the most relevant Candida species toward compound 4 using the method M27-A3 was evaluated. We observed among most of the clinical strains of C. albicans MIC ranging from 0.00195 to 0.0078 μg/mL. Compound 4 at 32 μg/mL exhibited fungicidal activity against nine Candida strains tested using the MFC assay. Compound 4 displayed anti-Candida activity (with clear endpoint) against 22% of clinical strains of Candida. Under compound 4, Candida susceptibility and tolerance, namely paradoxical effect (PG), was found for only two clinical isolates (C. glabrata and C. parapsilosis) and reference strain 14053 using both M27-A3 and MFC method. We found that compound 4 does not induce toxicity in vivo against larvae of Galleria mellonella (≥97% survival) and it displays reduced toxicity on mammalian cells in vitro (< CC20 at 64 μg/mL). Furthermore, XTT assay denoted clear metabolic activity of sessile cells in the presence of compound 4. Thus, the effect of compound 4 on formed C. albicans biofilms was minimal. Moreover, strain 90028 exhibited no defects in hyphal growth on Caco-2 monolayer under compound 4 influence at MIC = 16 μg/mL. The MIC values of compound 4 against C. albicans 90028, in medium with sorbitol did not suggest that compound 4 acts by inhibiting fungal cell wall synthesis. Our findings with compound 4 suggest a general strategy for antifungal agent development that might be useful in limiting the emergence of resistance in Candida strains.

Highlights

Members of the Candida genus are the third most common cause of hospital-acquired systemic infections, which are associated to high mortality rates worldwide (Falagas et al, 2010)
Endpoint was visible mostly for the latter strains at the range: 16–0.5 μg/mL compared with the remaining strains tested, it was evident that this effect appeared for C. krusei after the extension of the concentration tested to 0.00195 μg/mL (0.25 μg/mL = 100%)
The findings showed that compound 4 does not interfere with cell wall biosynthesis pathway because the susceptibility of yeast cells to it was unaltered in the presence or absence of an osmotic protector (Figure 4)

Summary

Introduction

Members of the Candida genus are the third most common cause of hospital-acquired systemic infections, which are associated to high mortality rates worldwide (Falagas et al, 2010). Novel β-Ketosulfone against Candida synthesis, pyrimidine salvage, or act by binding to ergosterol and cause osmotic leakage They are effective in the treatment of candidiasis, the main disadvantages of these antimycotics, are the high toxicity to host tissues, emergence of drug-resistant strains, and high costs (Rajeshkumar and Sundararaman, 2012). It has been reported that paradoxical growth could increase the probability of the appearance of stable resistance among fungal strains and treatment failure (Rueda et al, 2014). This phenomenon was described mainly to echinocandins and fluconazole at high concentrations (Chamilos et al, 2007; Zanette and Kontoyiannis, 2013). As its mechanisms are incompletely understood, further studies on the mechanism of the newly synthesized agents paradoxical effect in regard to different Candida species emerged from studies of other authors (Chamilos et al, 2007; Zanette and Kontoyiannis, 2013; Juvvadi et al, 2015)

Methods

Results

Conclusion