late genes in the ergosterol biosynthetic pathway of ..
The triazoles also secondarily target other steps in the ergosterol biosynthesis pathway.
in the ergosterol biosynthesis pathway ..
Since Erg2 is the primary target of morpholine drugs, our analysis of the inhibition profile of fenpropimorph in combination with FK506 or CsA established Erg2 as a good target for the development of antifungal drugs that participate in this synergy. However, we sought to investigate the practicality of specifically targeting Erg24, the secondary target of fenpropimorph. We independently confirmed the findings of Jia et al. () that erg24/erg24 mutants are hypersensitive to terbinafine and surprisingly found that these mutants were also rather sensitive to fenpropimorph compared to the wild-type strain (data not shown). Erg2 functions downstream of Erg24. Thus, if Erg24 is mutated or inhibited, why does blocking Erg2 activity have any effect on erg24/erg24 mutants? Although the ergosterol biosynthetic pathway is commonly depicted as a linear set of reactions (Fig. ), this pathway is an intricate network of enzymes and enzyme product interactions. Either the Erg2 enzyme functions in the absence of Erg24, or fenpropimorph has additional targets other than Erg2 and Erg24. Therefore, inhibiting the ERG24 gene product may also increase the sensitivity of C. albicans to a variety of ergosterol biosynthesis inhibitors. These results serve as evidence that the Erg24 enzyme is a practical target for antifungal drug combinations. With amorolfine only available as topical therapy and no other morpholines in clinical use, our data demonstrate the therapeutic potential of the development of systemically active morpholines as an alternative to azoles and amphotericin B therapy.
Azoles have been a predominant therapy for Candida infections for more than 20 years, but given the emergence of azole-resistant C. albicans strains and Candida species, there is a need for more antifungal drug options. Terbinafine acts upstream of the azole target Erg11 and fenpropimorph acts downstream of Erg11 in the ergosterol biosynthesis pathway (Fig. ). Like fluconazole, terbinafine and fenpropimorph have demonstrated synergy with both calcineurin inhibitors. Our in vitro studies have also shown that the combination of terbinafine or fenpropimorph and FK506 can significantly inhibit both C. glabrata and C. krusei. It is possible that this synergism may provide relief from the nephrotoxicity that results from amphotericin B therapy, the typical alternative to using azoles to treat these resistant species.
act in the ergosterol biosynthesis pathway…
first demonstrates the reliability of a new stratigraphictechnique for climatic assessment utilizing the relative abundance of two C37alkenones in marine sediments ().
First demonstration of a specific receptor-mediated release of 20:4n-6 and22:6n-3 from plasmalogen phospholipids ().
Evidence is given that phosphatidic acid is a lipid second messenger with growthfactor-like properties, stimulating the breakdown of phosphoinositides andcalcium release ().
Demonstration of an inhibition of protein kinase C by sphingosine whichsuggested an important role for that lipid in the regulation of the signaltransduction pathways (, ).
First clear demonstration of a formation of diacylglycerol as second messengerfrom phosphatidylcholine in hormone-stimulated cells ().
Abscisic acid, one of the most important phytohormones, has been shown to bepresent in the central nervous system of pigs and rats ().
After the discovery of 20:5n-3 in a marine bacterium (Johns RB et al., 1977), a study on 11 piezophilic bacteria (from 1200 to 10 476 m of sea depth) revealed they produced EPA (20:5n-3) and DHA (22:6n-3) in increasing proportion oftotal fatty acids when pressure increased ().
discovered in erythrocytes an ATP-dependent aminophospholipid-specific transporter (translocase) which transports phosphatidylserine and phosphatidylethanolamine from the outer to the inner leaflet of plasma membranes ().
Evidence was given for a post-translational modification of proteins byincorporation of isoprenoid lipids ().
New aldehydic products of the cyclooxygenase pathway, levuglandins, have beendiscovered
Candida albicans ergosterol biosynthesis
Pharmacokinetics of Azoles: Chemically, azoles are lipophilic weak bases. All azoles have good relative or absolute bioavailability after oral administration (except the capsule form of itraconazole). Dissolution of ketoconazole and itraconazole in the stomach, administered as solid oral dosage forms are significantly influenced by elevations in gastric pH 17, 18. Azoles (except posaconazole) require extensive oxidative (CYP) metabolism to be eliminated from the body 19, 20. Unlike the other triazoles, posaconazole undergoes minimal (2%) CYP metabolism; most of its metabolites are glucuronide conjugates formed by uridine diphosphate glucuronosyltransferase (UGT) pathways, mainly UGT1A4 21, 22.
Fungicidal synergism between azoles and calcineurin inhibitors has previously been demonstrated in C. albicans (, , , ). We hypothesized that this synergy might also exist between calcineurin inhibitors and other antifungal drugs that inhibit ergosterol biosynthesis in C. albicans. To determine whether synergism between calcineurin inhibitors and fenpropimorph or terbinafine occurs, we employed disk diffusion halo assays. Wild-type C. albicans strain SC5314 was grown in the presence or absence of FK506 or CsA with either fenpropimorph or terbinafine (Fig. ). Fenpropimorph or terbinafine alone exhibited only modest growth inhibition. As previously demonstrated by Cruz et al. (), neither FK506 nor CsA alone exhibited any in vitro growth inhibition of the Candida strains used in our study (see Fig. ; data not shown).
Ergosterol Biosynthesis Inhibitors Become Fungicidal …
ergosterol biosynthesis pathway, transporter genes, …
Ergosterol Biosynthesis Inhibitors Become Fungicidal when Combined with Calcineurin Inhibitors against Candida ..
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The ergosterol biosynthesis pathway, transporter genes, and azole resistance in Aspergillus fumigatus
Fluconazole/Azocan 200mg Capsules - - (eMC)
The expression of genes involved in the ergosterol biosynthesis pathway in Candida albicans and Candida ..
Fluconazole/Azocan 200mg Capsules - by FDC International Ltd
Azoles target the ergosterol biosynthetic enzyme lanosterol 14α-demethylase and are a widely applied class of antifungal agents because of their broad therapeutic window, wide spectrum of activity, and low toxicity. Unfortunately, azoles are generally fungistatic and resistance to fluconazole is emerging in several fungal pathogens. We recently established that the protein phosphatase calcineurin allows survival of Candida albicans during the membrane stress exerted by azoles. The calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506) are dramatically synergistic with azoles, resulting in potent fungicidal activity, and mutant strains lacking calcineurin are markedly hypersensitive to azoles. Here we establish that drugs targeting other enzymes in the ergosterol biosynthetic pathway (terbinafine and fenpropimorph) also exhibit dramatic synergistic antifungal activity against wild-type C. albicans when used in conjunction with CsA and FK506. Similarly, C. albicans mutant strains lacking calcineurin B are markedly hypersensitive to terbinafine and fenpropimorph. The FK506 binding protein FKBP12 is required for FK506 synergism with ergosterol biosynthesis inhibitors, and a calcineurin mutation that confers FK506 resistance abolishes drug synergism. Additionally, we provide evidence of drug synergy between the nonimmunosuppressive FK506 analog L-685,818 and fenpropimorph or terbinafine against wild-type C. albicans. These drug combinations also exert synergistic effects against two other Candida species, C. glabrata and C. krusei, which are known for intrinsic or rapidly acquired resistance to azoles. These studies demonstrate that the activity of non-azole antifungal agents that target ergosterol biosynthesis can be enhanced by inhibition of the calcineurin signaling pathway, extending their spectrum of action and providing an alternative approach by which to overcome antifungal drug resistance.
Ergosterol biosynthesis in novel melanized ..
N2 - Candida albicans is a leading human fungal pathogen that causes life-threatening systemic infections. A key regulator of C. albicans stress response, drug resistance, morphogenesis, and virulence is the molecular chaperone Hsp90. Targeting Hsp90 provides a powerful strategy to treat fungal infections, however, the therapeutic utility of current inhibitors is compromised by toxicity due to inhibition of host Hsp90. To identify components of the Hsp90-dependent circuitry governing virulence and drug resistance that are sufficiently divergent for selective targeting in the pathogen, we pioneered chemical genomic profiling of the Hsp90 genetic network in C. albicans. Here, we screen mutant collections covering ~10% of the genome for hypersensitivity to Hsp90 inhibition in multiple environmental conditions. We identify 158 HSP90 chemical genetic interactors, most of which are important for growth only in specific environments. We discovered that the sterol C-22 desaturase gene ERG5 and the phosphatidylinositol-4-kinase (PI4K) gene STT4 are HSP90 genetic interactors under multiple conditions, suggesting a function upstream of Hsp90. By systematic analysis of the ergosterol biosynthetic cascade, we demonstrate that defects in ergosterol biosynthesis induce cellular stress that overwhelms Hsp90's functional capacity. By analysis of the phosphatidylinositol pathway, we demonstrate that there is a genetic interaction between the PI4K Stt4 and Hsp90. We also establish that Stt4 is required for normal actin polarization through regulation of Wal1, and suggest a model in which defects in actin remodeling induces stress that creates a cellular demand for Hsp90 that exceeds its functional capacity. Consistent with this model, actin inhibitors are synergistic with Hsp90 inhibitors. We highlight new connections between Hsp90 and virulence traits, demonstrating that Erg5 and Stt4 enable activation of macrophage pyroptosis. This work uncovers novel circuitry regulating Hsp90 functional capacity and new effectors governing drug resistance, morphogenesis and virulence, revealing new targets for antifungal drug development.
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