Antifungal activity of some cyclooxygenase inhibitors on Candida albicans: PGE2-dependent mechanism

Abstract

Candida spp., such as Candida albicans, are opportunisticyeasts that cause mucocutaneous and systemic infections withhighmortalityandmorbidityrates(Carrillo-Munozetal. 2006).Prostaglandins (PG) are small lipid molecules that havediverse biological activities, including the modulation of hostimmune responses. Both the host cells and fungal pathogenare sources of PG during fungal infection (Noverr et al. 2001,2002). These purified fungal PG, partially characterized as aprostaglandin E (PGE), enhance germ tube formation in C.albicans and down-modulate chemokine and tumor necrosisfactor alpha (TNF-α) production in mammalian cells (Noverret al. 2001). Since nonsteroidal anti-inflammatory drugs(NSAIDs) inhibit cyclooxygenase (COX) enzymes and reducethe synthesis of PG (Vane and Botting 1998), which arerequired for the development of yeast, NSAIDs may haveantifungal activity. Some studies have showed the role ofNSAIDs on fungal growth inhibitory effect, fungal PGE2production, and enzyme activation (Alem and Douglas2004; Erb-Downward and Noverr2007; Erb-Downward etal. 2008; Trofa et al.2009; Ells et al. 2011). In this work,we investigated whether some COX inhibitors couldinhibit the growth of C. albicans invitrobyaPGE2-dependent mechanism.Materials and methodsOrganism, drugs, and stock solution C. albicans strainATCC 40175 was obtained from the National Institute forHealth Quality Control, Brazil. Stock solutions of 2 mmol/Laspirin (acetylsalicylic acid, Sigma Aldrich), 4 mmol/Libuprofen (Sigma Aldrich), and 1 mmol/L indomethacin(SigmaAldrich)werepreparedin50%ethanol.Inaddition,astock solution of 220 mmol/L sodium salicylate (SigmaAldrich) was prepared in sterile distilled water. For theexperiments, COX inhibitors were used at final concen-trations ranging from 1.1–22 mmol/L. PGE2 (CaymanChemicals, Ann Arbor, MI, USA) was dissolved in 50%ethanol and used at a final concentration of 10 ng/mL.Drug treatment of yeast cells and colony counts The yeastinoculum preparation and in vitro antimicrobial drug screen-ing were performed byusing the broth microdilution method,as described by the Clinical and Laboratory StandardsInstitute (2008). Recent culture, in log phase, of C. albicanswas used to prepare the cell suspension adjusted to 0.5