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Health Antifungal and Anti-Biofilm Effect of the Calcium Channel Blocker Verapamil on Non-Albicans Candida Species

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Health Antifungal and Anti-Biofilm Effect of the Calcium Channel Blocker Verapamil on Non-Albicans Candida Species An Acad Bras Cienc (2020) 92(4): e20200703 DOI 10.1590/0001-3765202020200703 Anais da Academia Brasileira de Ciências | Annals of the Brazilian Academy of Sciences Printed ISSN 0001-3765 I Online ISSN 1678-2690 www.scielo.br/aabc | www.fb.com/aabcjournal HEALTH SCIENCES Antifungal and anti-biofilm effect of Running title: Verapamil effect on the calcium channel blocker verapamil Candida non-albicans species on non-albicans Candida species Academy Section: Health LILIANA SCORZONI, RAQUEL T. DE MENEZES, THAIS CRISTINE PEREIRA, PRISCILA Sciences S. OLIVEIRA, FELIPE DE CAMARGO RIBEIRO, EVELYN LUZIA DE SOUZA SANTOS, LUCIANA R.O. FUGISAKI, LUCIANE D. DE OLIVEIRA & JOSÉ BENEDITO O. AMORIM e20200703 Abstract: Candida is a human fungal pathogen that causes a wide range of diseases. Candida albicans is the main etiologic agent in these diseases; however, infections can be caused by non-albicans Candida species. Virulence factors such as biofilm production, 92 which protect the fungus from host immunity and anti-fungal drugs, are important for the (4) 92(4) infection. Therefore, available antifungal drugs for candidiasis treatment are limited and the investigation of new and effective drugs is needed. Verapamil is a calcium channel blocker with an inhibitory effect on hyphae development, adhesion, and colonization of C. albicans. In this study, we investigated the effect of verapamil on cell viability and its antifungal and anti-biofilm activity in non-albicans Candida species. Verapamil was not toxic to keratinocyte cells; moreover, C. krusei, C. parapsilosis, and C. glabrata were susceptible to verapamil with a minimal inhibitory concentration (MIC) of 1250 μM; in addition, this drug displayed fungistatic effect at the evaluated concentrations. After treatment with verapamil, reduced viability, biomass, and mitochondrial activity were observed in biofilms of the non-albicans Candida species C. krusei, C. glabrata, and C. parapsilosis. These findings highlight the importance of the study of verapamil as an alternative treatment for infections caused by non-albicans Candida species. Key words: Verapamil, antifungal activity, biofilm, Candida non-albicans, drug repurposing. INTRODUCTION common species responsible for causing infections worldwide; however, there has been In the last decade, an increase in the incidence an increase in the incidence of infections of Candida spp. infections was observed; this caused by non-albicans Candida species (Alim was found to be associated with an increase in et al. 2018, Santolaya et al. 2019, Silva et al. the number of immunocompromised patients 2012). Candida albicans represents 50-82% of (Quindós et al. 2018, Salehi et al. 2019, Walsh et the Candida spp. isolates, while among non- al. 2019). Candida species are common human albicans species C. glabrata, C. krusei, and C. fungal pathogens that cause a wide range parapsilosis correspond to the 9.4-19%, 2-3%, of clinical diseases, ranging from superficial and 1-2%, respectively (Dos Santos Abrantes et infections to life-threatening systemic disease al. 2014, Thompson et al. 2010). (Lin et al. 2018, Meletiadis et al. 2017, Pfaller & The use of steroid drugs or broad-spectrum Diekema 2007). Candida albicans is the most antibiotics, as well as smoking, carrying An Acad Bras Cienc (2020) 92(4) LILIANA SCORZONI et al. VERAPAMIL EFFECT ON CANDIDA NON-albicans SPECIES prostheses, and possessing a compromised predisposing the organism to develop resistance immune system are risk factors for the against these drugs (genetic resistance) (Ciofu production of a microenvironment that favors et al. 2017). the overgrowth of Candida spp. This may trigger In addition, the biofilm formation allows oral candidiasis, which is the most prevalent microorganisms to resist hostile environmental opportunistic fungal infection affecting the oral conditions such as starvation and desiccation, mucosa (Singh et al. 2014). Oral candidiasis is and causes a wide range of chronic diseases. mainly caused by overgrowth of C. albicans; Consequently, biofilms are a major source however, non-albicans species have been of persistent nosocomial infections in isolated as well in samples of oropharyngeal immunosuppressed patients (Davies 2003, Singh candidiasis (Patel et al. 2012, Singh et al. 2014). et al. 2000) who come in contact with medical Oral candidiasis associated with Candida spp. devices, such as catheters, cardiac pacemakers, can be classified as pseudomembranous, joint prosthesis, dentures, prosthetic heart erythematous, nodular, or plaque-like. valves, and contact lenses (Piozzi et al. 2004, Wu Depending on the host’s immune system, oral et al. 2015), that are known to provide an ideal candidiasis may become systemic by spreading surface for the attachment of microorganisms. into the bloodstream or gastrointestinal tract, Saliva contains molecules that reduce the leading to a serious infection that can cause the adhesion of microorganisms, but in contrast death of the individual (Akpan & Morgan 2002, also produces salivary proteins that have Niimi et al. 2010). been shown to act as microbial receptors, thus One of the most studied Candida spp. facilitating the formation of biofilms in the oral virulence factors are biofilms, i.e., sessile cavity (Junqueira 2012). communities of microbes found either attached Consequently, the treatment and effective to a surface or buried firmly in an extracellular elimination of fungal biofilms has become matrix (ECM), which is a complex and highly a challenge (Roy et al. 2018). Earlier studies polar mixture of biomolecules including showed that elimination of biofilms requires proteins, polysaccharides, nucleic acids, and higher concentrations of antimicrobials than the lipids (Overhage et al. 2008) conventional dose (Bjarnsholt et al. 2009, Brandl The biofilm matrices of Candida species et al. 2008, Hoyle & Costerton 1991, Parsek & have a strong network of exopolymers, providing Singh 2003, Rasmussen & Givskov 2006, Wu et al. protection against host and environmental 2015). The effect of antifungal drugs on biofilms factors, such as the immune system and depends on the class on the antifungal, as well antimicrobial drugs. Although biofilm matrices as on the antifungal susceptibility of the species do not inhibit the diffusion of antibiotics, they and the isolate (Taff et al. 2013). Recent studies restrict antibiotic entry into the biofilm. Matrix demonstrated that fluconazole can reduce components like exopolymers hinder the biomass and cell number in Candida spp. biofilms diffusion of drugs into the cells of the biofilm from fluconazole-susceptible and -resistantC. by binding to them, making the fungi refractory albicans and C. glabrata isolates, albeit in a high to antifungals (Al-Fattani & Douglas 2004, concentration (from 40 µg/mL to 1,280 µg/mL, Dominguez et al. 2018, Rodrigues et al. 2017). This depending on the isolate) corresponding to five property of biofilms leads to persistent biofilm times the previously reported Minimal Inhibitory infections, despite treatment with antibiotics, Concentration (MIC) of Panariello et al. (2018). An Acad Bras Cienc (2020) 92(4) e20200703 2 | 14 LILIANA SCORZONI et al. VERAPAMIL EFFECT ON CANDIDA NON-albicans SPECIES Furthermore, amphotericin B in liposomal or Memorial Institute 1640 (RPMI 1640) medium. deoxycholate formulation was active against The maximum DMSO concentration in the final C. albicans, C. glabrata, C. parapsilosis, and medium was 5%. C. tropicalis biofilms when administered in a concentration between four and eight times Evaluation of cell viability (in vitro cytotoxicity) greater than the reported MIC concentration using resazurin (2-8 mg/L). In addition, C. glabrata was the least Evaluation of cell viability was performed using susceptible yeast species to both evaluated the resazurin method. For this assay, the HaCaT formulations (Rodrigues & Henriques 2017). cell line (human keratinocytes) was purchased Finally, echinocandins represent the first choice from the Rio de Janeiro Cell Bank (BCRJ) and in the treatment of biofilm-relatedCandida spp. was maintained in Dulbecco’s Modified Eagle infections (Almirante et al. 2017); however, lack of Medium (DMEM) supplemented with 10% fetal effectiveness of echinocandin drugs against C. bovine serum and 2% antibiotics (100 μg/mL parapsilosis biofilm has been reported (Thomaz penicillin and 100 μg/mL streptomycin). HaCaT et al. 2020). Therefore, the search for alternative cells were seeded at a concentration of 106 drugs that could disperse and eliminate biofilms cells/mL in a 96-well microplate and incubated is warranted. for 24 h at 37 °C with 5% CO2. Cells were treated Drug repurposing consists of investigating with verapamil concentrations ranging from 2.4 new uses for already approved drugs to treat to 1250 μM for 24 h. Resazurin (Sigma-Aldrich, St another disease (Ashburn & Thor 2004). This Louis, MO) was used to measure cell viability as strategy could be used as an alternative to de described earlier (Pavan et al. 2010). According novo drug development to treat fungal diseases. to ISO 10993-5 (2009), drug concentrations Verapamil is a calcium channel blocker that provoking a >30% reduction in cell viability are is widely used in the treatment of angina and considered cytotoxic. hypertension (Fahie & Cassagnol 2020). This compound has an inhibitory effect on hyphae Microorganisms and culture conditions development, adhesion, and colonization of C. Candida krusei ATCC 6258, C. parapsilosis ATCC albicans (Yu et al. 2013, 2014a,
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