Potentiation of Azole Antifungals by 2-Adamantanamine

Abstract

e Azoles are among the most successful classes of antifungals. They act by inhibiting ␣-14 lanosterol demethylase in the ergosterol biosynthesis pathway. Oropharyngeal candidiasis (OPC) occurs in about 90% of HIV-infected individuals, and 4 to 5% are refractory to current therapies, including azoles, due to the formation of resistant biofilms produced in the course of OPC. We reasoned that compounds affecting a different target may potentiate azoles to produce increased killing and an antibiofilm therapeutic. 2-Adamantanamine (AC17) was identified in a screen for compounds potentiating the action of miconazole against biofilms of Candida albicans. AC17, a close structural analog to the antiviral amantadine, did not affect the viability of C. albicans but caused the normally fungistatic azoles to become fungicidal. Transcriptome analysis of cells treated with AC17 revealed that the ergosterol and filamentation pathways were affected. Indeed, cells exposed to AC17 had decreased ergosterol contents and were unable to invade agar. In vivo, the combination of AC17 and fluconazole produced a significant reduction in fungal tissue burden in a guinea pig model of cutaneous candidiasis, while each treatment alone did not have a significant effect. The combination of fluconazole and AC17 also showed improved efficacy (P value of 0.018) compared to fluconazole alone when fungal lesions were evaluated. AC17 is a promising lead in the search for more effective antifungal therapeutics.

Artemisinins, New Miconazole Potentiators Resulting in Increased Activity against Candida albicans Biofilms

“…This concept has also recently gained a lot of attention in anti-Candida research (20)(21)(22)(23)(24)(25). Repurposing of known drugs is favorable from an economic perspective.…”

“…For example, toremifene citrate (a selective estrogen receptor modulator used in the treatment of breast cancer) has been reported to be a good potentiator of amphotericin B and caspofungin, but not of azoletype antifungals, against Candida albicans biofilms (20). Potentiation of azole antifungals by 2-adamantanamine, a derivative of amantadine (an anti-influenza A virus drug also used to treat some of the symptoms of Parkinson's disease), against C. albicans biofilms was recently demonstrated, suggesting the opportunity to repurpose (analogues of) other FDA-approved medications (22).…”

Assessment and Optimizations of Candida albicans In Vitro Biofilm Assays

“…The findings from these assays were then verified using in vivo models (13)(14)(15)(16)(17)(18)(19)(20)(21). Likewise, in vitro assays have been used as the initial step to identify compounds that inhibit and/or disrupt biofilm formation before the compounds are tested for toxicity in cell culture and in in vivo models (22)(23)(24)(25). Although there are variations in methodology among the different in vitro biofilm assays, at the most basic level they all involve similar steps: initial adherence of cells to a surface coupled with washing to remove nonadhered or weakly adhered cells, followed by a growth step that can vary in length depending on the assay.…”

Discovery of New Imidazole Derivatives Containing the 2,4-Dienone Motif with Broad-Spectrum Antifungal and Antibacterial Activity

“…Therefore, a large number of antimicrobial drugs have been listed, which play an important role in treating infections [1]. As the need for antifungal intervention has increased, so too has the prevalence of resistance [2]. With the irrational use of antibiotics, the resistance of microorganisms has become a very serious clinical problem.…”

“…Their extensive applications, especially as antifungal agents, are frequently investigated, and this has become one of the most active areas in antifungal drug development. Many imidazole-based derivatives have been marketed as antifungal drugs such as ketoconazole (1), miconazole (2), clotrimazole (3), tioconazole (4), econazole (5), tinidazole (6), enilconazole/imazalil (7), parconazole (8), eberconazole (9), lanoconazole (10), fenticonazole (11), bifonazole (12), sulconazole (13), lombazole (14), and sertaconazole (15) (Figure 1) [13][14][15][16][17][18][19], which indicates their large development value and broad potential as antifungal agents. The imidazole ring has been demonstrated to be a versatile core of many biologically active molecules, especially those with antifungal properties.…”