Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade—A Review

Abstract

Candida is an important opportunistic fungal pathogen, especially in biofilm associated infections. The formation of a Candida biofilm can decrease Candida sensitivity to antifungal drugs and cause drug resistance. Although many effective antifungal drugs are available, their applications are limited due to their high toxicity and cost. Seeking new antifungal agents that are effective against biofilm-associated infection is an urgent need. Many research efforts are underway, and some progress has been made in this field. It has been shown that the arachidonic acid cascade plays an important role in fungal morphogenesis and pathogenicity. Notably, prostaglandin E2 (PGE2) can promote the formation of a Candida biofilm. Recently, the inhibition of PGE2 has received much attention. Studies have shown that cyclooxygenase (COX) inhibitors, such as aspirin, ibuprofen, and indomethacin, combined with fluconazole can significantly reduce Candida adhesion and biofilm development and increase fluconazole susceptibility; the MIC of fluconazole can be decrease from 64 to 2 μg/ml when used in combination with ibuprofen. In addition, in vivo studies have also confirmed the antifungal activities of these inhibitors. In this article, we mainly review the relationship between PGE2 and Candida biofilm, summarize the antifungal activities of COX inhibitors and analyze the possible antifungal activity of microsomal prostaglandin E synthase-1 (MPGES-1) inhibitors; additionally, other factors that influence PGE2 production are also discussed. Hopefully this review can disclose potential antifungal targets based on the arachidonic acid cascade and provide a prevailing strategy to alleviate Candida albicans biofilm formation.

Synergistic Antifungal Effect of Fluconazole Combined with Licofelone against Resistant Candida albicans

“…In several studies, the synergistic effects of cyclooxygenase (COX) inhibitors combined with antifungal drugs against C. albicans biofilm and planktonic cells have been observed. These potential antifungal activities are supposed to be associated with the regulation of PGE 2 production ( Alem and Douglas, 2004 ; de Quadros et al, 2011 ; Rusu et al, 2014 ; Liu et al, 2016 ). A dual mPGES-1/LOX inhibitor, licofelone can suppress PGE 2 formation ( Koeberle et al, 2008 ) and has recently succeeded in reaching the required criteria in phase III clinical trials for osteoarthritis ( Payandemehr et al, 2015 ), but no researches in regards with its antifungal activity and mechanism against planktonic and biofilm cells of C. albicans have been carried out so far.…”

The Pharmaceutical Ability of <em>Pistacia lentiscus</em> L. Leaves Essential Oil against Periodontal Bacteria and Candida sp. and Its Anti-inflammatory Potential

“…In fact, Candida tends to withstand anti-fungal treatments especially when biofilms are formed. This is probably due to the ability of the yeast to produce high quantity of fungal PGE2, which also exhibits cross-reactivity with that of the host [9]. The issues are increased because of the side effects of antifungal therapies in humans, which may occur due to the poor ability of the drugs to target selectively the fungal cell [9].…”

“…Following epithelial cell harming by pathogenic agents, the inflammatory process sets off and pro-inflammatory cytokines are released to start the healing process [1,[7][8]. However, under these physio-pathological conditions, a severe and recurrent inflammation can be concomitant with periodontitis and oral Candidiasis [9][10], and may contribute to deleterious consequences. A lasting oxidation of arachidonic acid by cyclooxygenases (COX-1 and COX-2) and lipoxygenase (5-LOX) leads to the accumulation of prostaglandins, and leukotrienes [11][12].…”

Recognition of Candida albicans and Role of Innate Type 17 Immunity in Oral Candidiasis

“…In addition, increased prostaglandin levels during fungal infections can exacerbate fungal colonization and trigger chronic infection [58]. Thus, different enzymes of arachidonic acid pathways, for instance cPLA2α, can serve as a target for the development of new therapeutic strategies against C. albicans [62]. Altogether, this may constitute the object of future studies.…”