Susceptibility of Candida albicans to New Synthetic Sulfone Derivatives

Abstract

The influence of halogenated methyl sulfones, i.e. bromodichloromethyl-4-chloro-3-nitrophenyl sulfone (named halogenated methyl sulfone 1), dichloromethyl-4-chloro-3-nitrophenyl sulfone (halogenated methyl sulfone 2), and chlorodibromomethyl-4-hydrazino-3-nitrophenyl sulfone (halogenated methyl sulfone 3), on cell growth inhibition, aspartic protease gene (SAP4-6) expression, adhesion to epithelium, and filamentation was investigated. Antifungal susceptibility of the halogenated methyl sulfones was determined with the M27-A3 protocol in the range of 16-0.0313 µg/mL. Adherence to Caco-2 cells was performed in 24-well plates; relative quantification was normalized against ACT1 in cells after 18 h of growth in YEPD and on Caco-2 cells. SAP4-6 expression was analyzed using RT-PCR. Structure-activity relationship studies suggested that halogenated methyl sulfone 1 containing bromodichloromethyl or dichloromethyl function at C-4 (halogenated methyl sulfone 2) of the phenyl ring showed the best activity (100% cell inhibition at 0.5 µg/mL), while hydrazine at C-1 (halogenated methyl sulfone 3) reduced the sulfone potential (100% = 4 µg/mL). SAP4-6 were up- or down-regulated depending on the strains' genetic background and the substitutions on the phenyl ring. Halogenated methyl sulfone 2 repressed germination and affected adherence to epithelium (P ≤ 0.05). The tested halogenated methyl sulfones interfered with the adhesion of Candida albicans cells to the epithelial tissues, without affecting their viability after 90 min of incubation. The mode of action of the halogenated methyl sulfones was attributed to the reduced virulence of C. albicans. SAP5 and SAP6 contribute to halogenated methyl sulfones resistance. Thus, halogenated methyl sulfones can inhibit biofilm formation due to their interference with adherence and with the yeast-to-hyphae transition.

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

“…Considering the structure-dependent effect, we propose that the presence of bromine and chlorine moiety attached to C 2 of phenyl ring in compound 4 may be the reason of its high antifungal activity (Bondaryk et al, 2015). As we showed previously, these elements are important for the interactions with fungal cells (Bondaryk et al, 2015; Staniszewska et al, 2015a,b). Indeed, bromodichloro- and dichloro-methyl substituents have a crucial role for reducing morphogenesis and adhesion of C. albicans without enhanced toxicity.…”

“…Moreover, structural analyses revealed that compound 4 -treated biofilms showed minor defects in the biofilm architecture (Figure 7). In our opinion, the reintroduction of fluorine atom instead of chlorine at the C 4 position of the benzene ring can exert activity against Candida sessile cells (Bondaryk et al, 2015; Staniszewska et al, 2015a,b). Candida albicans biofilm heterogeneity has a direct impact on antifungal sensitivity to compound 4 , based on our in vitro study.…”

“…Candida albicans is polymorphic fungus with the ability to form yeast and hyphal cells, both critical for biofilm development and maintenance (Gulati and Nobile, 2016). Our recent studies (Bondaryk et al, 2015; Staniszewska et al, 2015a,b) demonstrated that inhibition of hyphal growth attenuated virulence in an in vitro model of superficial candidiasis, and a disruption of this cellular process might serve as an effective therapeutic intervention. Thus, inhibition of dimorphism may provide an alternative approach allowing finding compounds with the potential to control C. albicans infections (Lu et al, 2014).…”

“…In light of this, it has become essential to develop new drugs designed to circumvent resistance or target alternative cellular processes. Our early reports on the antifungal potential of the newly synthesized halogenated methyl sulfones (Staniszewska et al, 2015a,b) has spurred significant interest in the synthesis of new α-chloro β-keto-based sulfone which may offer improved antifungal activity.…”

Atividade Inibitória De Óleos Essenciais Vegetais Frente À Candida Glabrata, Resistente a Fluconazol

“…Dentre os principais fármacos empregados, deve-se citar a nistatina e o fluoconazol 4 . Entretanto, o uso difundido e não controlado de tais fármacos podem induzir ao surgimento de cepas com resistência medicamentosa 6 , a exemplo da C. glabrata, resistente aos derivados azóis, como fluconazol e itraconazol 7 . Desta forma, a busca por novas substâncias capazes de controlar e debelar a infecção tem sido avaliada.…”