A Decade of Antifungal Leads from Natural Products:2010-2019

In this review, we discuss novel natural products discovered within the last decade that are reported to have antifungal activity against pathogenic species. Nearly a hundred natural products were identified that originate from bacteria, algae, fungi, sponges, and plants. Fungi were the most prolific source of antifungal compounds discovered during the period of review. The structural diversity of these antifungal leads encompasses all the major classes of natural products including polyketides, shikimate metabolites, terpenoids, alkaloids, and peptides

Platination de l'ADN télomérique (des structures quadruplexes au double brin)

Les télomères sont des complexes nucléoprotéiques composés de séquences riches en guanines, double brin et simple brin. Ce dernier peut adopter des structures particulières, les structures quadruplexes qui sont des cibles pharmacologiques intéressantes car leur stabilisation entraîne l'inhibition de la télomérase, enzyme impliquée dans la prolifération des cellules cancéreuses. Les protéines TRF1 et TRF2 sont essentielles aux fonctions principales des télomères : la protection et le maintien de l'intégrité des chromosomes. Le c/s-platine est un agent anticancéreux utilisé en clinique depuis 1979 qui se fixe spécifiquement sur les N7 des guanines. Les télomères semblent donc être des cibles privilégiées du c/s-platine. In vitro, les complexes de platine permettent de stabiliser les structures quadruplexes et empêchent la fixation des protéines TRF1 et TRF2. In vivo, la fixation des complexes de platine devrait donc induire la déstabilisation et donc le dysfonctionnement des télomères.Telomeric DMA consists of highly repetitive short sequences of guanines residues followed by single-stranded DNA at the 3' end. In the presence of monovalent cations, the single strand is able to adopt stable quadruplex structures that were shown to inhibit telomerase, an enzyme involved in the immortalisation of cancerous cells. Proteins TRF1 and TRF2 are essential for the main function of telomeres: the protection of telomeres and the preservation of their integrity. Cis-platin is an antitumour drug used since 1979 in cancer therapy; it binds preferentially to guanines. Telomeric DNA appears as a potential target of this complex. In vitro, platinum complexes stabilise quadruplex structure and impede TRF1 and TRF2 binding. In vivo, the platination of telomeric DNA should interfere with the telomere integrity either by blocking the quadruplex structure or by impeding the binding of TRF1 and TRF2 and should provoke telomere destabilisation and dysfunction.PARIS-BIUP (751062107) / SudocSudocFranceF

Telomere Strand-Specific Length Analysis by Fluorescent In Situ Hybridization (Q-CO-FISH)

International audienc

Telomere Strand-Specific Length Analysis by Fluorescent In Situ Hybridization (Q-CO-FISH)

International audienc

Telomere Length Analysis by Quantitative Fluorescent in Situ Hybridization (Q-FISH)

International audienc

Biological exploration of a novel 1,2,4-triazole-indole hybrid molecule as antifungal agent

International audience(2-(2,4-Dichlorophenyl)-3-(1H-indol-1-yl)-1-(1,2,4-1H-triazol-1-yl)propan-2-ol (8 g), a new 1,2,4-triazole-indole hybrid molecule, showed a broad-spectrum activity against Candida, particularly against low fluconazole-susceptible species. Its activity was higher than fluconazole and similar to voriconazole on C. glabrata (MIC90 = 0.25, 64 and 1 µg/mL, respectively), C. krusei (MIC90 = 0.125, 64 and 0.125 µg/mL, respectively) and C. albicans (MIC90 = 0.5, 8 and 0.25 µg/mL, respectively). The action mechanisms of 8 g were also identified as inhibition of ergosterol biosynthesis and phospholipase A2-like activity. At concentration as low as 4 ng/mL, 8g inhibited ergosterol production by 82% and induced production of 14a-methyl sterols, that is comparable to the results obtained with fluconazole at higher concentration. 8 g demonstrated moderate inhibitory effect on phospholipase A2-like activity being a putative virulence factor. Due to a low MRC5 cytotoxicity, this compound presents a high therapeutic index. These results pointed out that 8 g is a new lead antifungal candidate with potent ergosterol biosynthesis inhibition

Platination of telomeric DNA by cisplatin disrupts recognition by TRF2 and TRF1

Telomeres, the nucleoprotein complexes located at the ends of chromosomes, are involved in chromosome protection and genome stability. Telomeric repeat binding factor 1 (TRF1) and telomeric repeat binding factor 2 (TRF2) are the two telomeric proteins that bind to duplex telomeric DNA through interactions between their C-terminal domain and several guanines of the telomeric tract. Since the antitumour drug cisplatin binds preferentially to two adjacent guanines, we have investigated whether cisplatin adducts could affect the binding of TRF1 and TRF2 to telomeric DNA and the property of TRF2 to stimulate telomeric invasion, a process that is thought to participate in the formation of the t-loop. We show that the binding of TRF1 and TRF2 to telomeric sequences selectively modified by one GG chelate of cisplatin is markedly affected by cisplatin but that the effect is more drastic for TRF2 than for TRF1 (3-5-fold more sensitivity for TRF2 than for TRF1). We also report that platinum adducts cause a decrease in TRF2-dependent stimulation of telomeric invasion in vitro. Finally, in accordance with in vitro data, analysis of telomeric composition after cisplatin treatment reveals that 60% of TRF2 dissociate from telomeres

Impact of TR34/L98H, TR46/Y121F/T289A and TR53 Alterations in Azole-Resistant Aspergillus fumigatus on Sterol Composition and Modifications after In Vitro Exposure to Itraconazole and Voriconazole

International audienceBackground: Sterols are the main components of fungal membranes. Inhibiting their biosynthesis is the mode of action of azole antifungal drugs that are widely used to treat fungal disease including aspergillosis. Azole resistance has emerged as a matter of concern but little is known about sterols biosynthesis in azole resistant Aspergillus fumigatus. Methods: We explored the sterol composition of 12 A. fumigatus isolates, including nine azole resistant isolates with TR34/L98H, TR46/Y121F/T289A or TR53 alterations in the cyp51A gene and its promoter conferring azole resistance. Modifications in sterol composition were also investigated after exposure to two azole drugs, itraconazole and voriconazole. Results: Overall, under basal conditions, sterol compositions were qualitatively equivalent, whatever the alterations in the target of azole drugs with ergosterol as the main sterol detected. Azole exposure reduced ergosterol composition and the qualitative composition of sterols was similar in both susceptible and resistant isolates. Interestingly TR53 strains behaved differently than other strains. Conclusions: Elucidating sterol composition in azole-susceptible and resistant isolates is of interest for a better understanding of the mechanism of action of these drugs and the mechanism of resistance of fungi