Boric acid is fungistatic to fungicidal depending on concentration and temperature. Inhibition of oxidative metabolism appears to be a key antifungal mechanism, but inhibition of virulence probably contributes to therapeutic efficacy in vivo.

Three Candida albicans strains were tested in the presence of 17-beta-estradiol (10-6 M and 10-9 M) for increased growth and for enhanced survival during incubation at nonpermissive temperatures. All 3 test organisms showed increased growth in the presence of estradiol compared with estrogen-free controls. Likewise, all 3 strains, when treated with estradiol, survived incubation at 48 degrees C better than did controls. Cytoplasmic extracts were probed with an anti-hsp90 antibody, and results suggested that intracellular hsp90 was up-regulated in the presence of 10-9 M 17-beta-estradiol. The results were confirmed by reverse-transcriptase polymerase chain reaction with primers specific for C. albicans hsp90. A kinetic study revealed that peak hsp90 expression occurred within 2 h of exposure to 17-beta-estradiol. In addition, estrogen increased the amount of cdr1 (Candida multidrug resistance) mRNA compared with cells not treated with estrogen. Coumarin and phenol also up-regulated hsp90 and cdr1 mRNAs, indicating that the estrogen-sensing and -response systems in C. albicans may lack specificity.

The Candida albicans CDR1 gene, encoding an ABC transporter that functions as an efflux pump, is thought to be involved in pathogenic adaptation and uses mammalian hormones and other environmental cues to regulate its activity. Exposure of several clinical isolates of C. albicans to 1 × 10 −8 M 17β-oestradiol increased CDR1 expression and the isolates showed a positive correlation between oestrogen induction of CDR1 and growth in the presence of oestrogen. A reporter strain carrying the GFP gene under the control of the CDR1 promoter was used to analyse the effect of steroid hormones and antifungal drugs on CDR1 expression by flow cytometry. We found that among the many hormones tested, only oestradiol and progesterone induce CDR1 expression. CDR1 induction requires hormone concentrations greater than 10 −8 M, a threshold reached in vivo only by progesterone. Using the GFP-reporter strain, we show CDR1 induction by female but not male human serum and demonstrate that exposure of C. albicans to physiological concentrations of progesterone measurably increases resistance to fluconazole, miconazole and 5-fluorouracil. Simultaneous exposure of C. albicans to hormones and antifungal drugs provided evidence that both agents induce CDR1 expression via different mechanisms with different saturation points.

Indoximod has shaped our understanding of the biology of IDO1 in the control of immune responses, though its mechanism of action has been poorly understood. Previous studies demonstrated that indoximod creates a tryptophan (Trp) sufficiency signal that reactivates mTOR in the context of low Trp concentrations, thus opposing the effects caused by IDO1. Here we extend the understanding of indoximod's mechanism of action by showing that it has pleiotropic effects on immune regulation. Indoximod can have a direct effect on T cells, increasing their proliferation as a result of mTOR reactivation. Further, indoximod modulates the differentiation of CD4 + T cells via the aryl hydrocarbon receptor (AhR), which controls transcription of several genes in response to different ligands including kynurenine (Kyn). Indoximod increases the transcription of RORC while inhibiting transcription of FOXP3, thus favoring differentiation to IL-17-producing helper T cells and inhibiting the differentiation of regulatory T cells. These indoximod-driven effects on CD8 +and CD4 + T cells were independent from the activity of IDO/TDO and from the presence of exogenous Kyn, though they do oppose the effects of Kyn produced by these Trp catabolizing enzymes. Indoximod can also downregulate expression of IDO protein in vivo in murine lymph node dendritic cells and in vitro in human monocyte-derived dendritic cells via a mechanism that involves signaling through the AhR. Together, these data improve the understanding of how indoximod influences the effects of IDO, beyond and distinct from direct enzymatic inhibition of the enzyme.

Object. To determine if tetracycline, previously reported to increase the probability of developing symptomatic vaginal yeast infections, has a direct effect on Candida albicans growth or induction of virulent phenotypes. Method. In vitro, clinical isolates of yeast were cultivated with sublethal concentrations of tetracycline and yeast cell counts, hyphal formation, drug efflux pump activity, biofilm production, and hemolysin production were determined by previously reported methods. Results. Tetracycline concentrations above 150 μg/mL inhibited Candida albicans, but at submicrogram/mL, a modest growth increase during the early hours of the growth curve was observed. Tetracycline did not inhibit hyphal formation at sublethal concentrations. Hypha formation appeared augmented by exposure to tetracycline in the presence of chemically defined medium and especially in the presence of human serum. Efflux pump CDR1 was upregulated and a nonsignificant trend toward increased biofilm formation was noted. Conclusion. Tetracycline appears to have a small growth enhancing effect and may influence virulence through augmentation of hypha formation, and a modest effect on drug efflux and biofilm formation, although tetracycline did not affect hemolysin. It is not clear if the magnitude of the effect is sufficient to attribute vaginitis following tetracycline treatment to direct action of tetracycline on yeast.