Despite their role in host nutrition, the anaerobic gut fungal (AGF) component of the herbivorous gut microbiome remains poorly characterized. Here, to examine global patterns and determinants of AGF diversity, we generate and analyze an amplicon dataset from 661 fecal samples from 34 mammalian species, 9 families, and 6 continents. We identify 56 novel genera, greatly expanding AGF diversity beyond current estimates (31 genera and candidate genera). Community structure analysis indicates that host phylogenetic affiliation, not domestication status and biogeography, shapes the community rather than. Fungal-host associations are stronger and more specific in hindgut fermenters than in foregut fermenters. Transcriptomics-enabled phylogenomic and molecular clock analyses of 52 strains from 14 genera indicate that most genera with preferences for hindgut hosts evolved earlier (44-58 Mya) than those with preferences for foregut hosts (22-32 Mya). Our results greatly expand the documented scope of AGF diversity and provide an ecologically and evolutionary-grounded model to explain the observed patterns of AGF diversity in extant animal hosts.

In spite of their indispensable role in host nutrition, the anaerobic gut fungal (AGF) component of the herbivorous gut microbiome remains poorly characterized. To examine global patterns and determinants of AGF diversity, we generated and analyzed an amplicon dataset from 661 fecal samples from 34 animal species, 9 families, and 6 continents. We identified 56 novel genera, greatly expanding AGF diversity beyond current estimates. Both stochastic (homogenizing dispersal and drift) and deterministic (homogenizing selection) processes played an integral role in shaping AGF communities, with a higher level of stochasticity observed in foregut fermenters. Community structure analysis revealed a distinct pattern of phylosymbiosis, where host-associated (animal species, family, and gut type), rather than ecological (domestication status and biogeography) factors predominantly shaped the community. Hindgut fermenters exhibited stronger and more specific fungal-host associations, compared to broader mostly non-host specific associations in foregut fermenters. Transcriptomics-enabled phylogenomic and molecular clock analyses of 52 strains from 14 genera indicated that most genera with preferences for hindgut hosts evolved earlier (44–58 Mya), while those with preferences for foregut hosts evolved more recently (22–32 Mya). This pattern is in agreement with the sole dependence of herbivores on hindgut fermentation past the Cretaceous-Paleogene (K-Pg) extinction event through the Paleocene and Eocene, and the later rapid evolution of animals employing foregut fermentation strategy during the early Miocene. Only a few AGF genera deviated from this pattern of co-evolutionary phylosymbiosis, by exhibiting preferences suggestive of post-evolutionary environmental filtering. Our results greatly expand the documented scope of AGF diversity and provide an ecologically and evolutionary-grounded model to explain the observed patterns of AGF diversity in extant animal hosts.

A series of new fluoroquinolone conjugates 8a-g and 9a-f were synthesized via benzotriazole-mediated synthetic approach with good yield and purity. Some of the synthesized analogs exhibited significant antibacterial properties against Escherichia coli and Staphylococcus aureus with potency higher than that of the parent drugs through in vitro standard bioassay procedure (conjugates 8c and 8d reveal antimicrobial properties with potency 1.9, 61.9, 20.7 and 2.4, 37.1, 8.3 folds relative to the parent antibiotic 6 against E. coli, S. aureus, and Enterococcus faecalis, respectively). The observed experimental data were supported by enzymatic DNA gyrase inhibitory property. Developed BMLR-QSAR model validates the observed experimental data and recognizes the parameters responsible for the enhanced antibacterial properties. K E Y W O R D S antibacterial, dichloroacetic acid, DNA gyrase, fluoroquinolone, hybrid conjugates F I G U R E 1 Examples of different class of antibiotics 250 | SELIEM Et aL.to microwave irradiation (Discover mode; run time: 60 s; Power Max-cooling mode). N-(Boc-aminoacyl)benzotriazoles 10a-g (Panda, Hall, et al., 2014; Panda, Naumov, et al., 2014) Compounds 10a-g were synthesized by irradiating an equimolar amount of Boc-protected amino acid with 1-(methylsulfonyl)-1H-benzo[d] [1,2,3]triazole (BtSO 2 Me) in the presence of 2.0 eq. of triethylamine for 2 min run time and 60 min hold time at 70°C and 50 W irradiation power. Completion of the reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with water. The product obtained was extracted with ethyl acetate and then washed with a saturated solution of sodium carbonate and water to afford compound 10a-g. | General procedure for the preparation of

In spite of their indispensable role in host nutrition, the anaerobic gut fungal (AGF) component of the herbivorous gut microbiome remains poorly characterized. To examine global patterns and determinants of AGF diversity, we generated and analyzed an amplicon dataset from 661 fecal samples from 34 animal species, 9 families, and 6 continents. We identified 56 novel genera, greatly expanding AGF diversity beyond current estimates. Both stochastic (homogenizing dispersal and drift) and deterministic (homogenizing selection) processes played an integral role in shaping AGF communities, with a higher level of stochasticity observed in foregut fermenters. Community structure analysis revealed a distinct pattern of phylosymbiosis, where host-associated (animal species, family, and gut type), rather than ecological (domestication status and biogeography) factors predominantly shaped the community. Hindgut fermenters exhibited stronger and more specific fungal-host associations, compared to broader mostly non-host specific associations in foregut fermenters. Transcriptomics-enabled phylogenomic and molecular clock analyses of 52 strains from 14 genera indicated that most genera with preferences for hindgut hosts evolved earlier (44-58 Mya), while those with preferences for foregut hosts evolved more recently (22-32 Mya). This pattern is in agreement with the sole dependence of herbivores on hindgut fermentation past the Cretaceous-Paleogene (K-Pg) extinction event through the Paleocene and Eocene, and the later rapid evolution of animals employing foregut fermentation strategy during the early Miocene. Only a few AGF genera deviated from this pattern of co-evolutionary phylosymbiosis, by exhibiting preferences suggestive of post-evolutionary environmental filtering. Our results greatly expand the documented scope of AGF diversity and provide an ecologically and evolutionary-grounded model to explain the observed patterns of AGF diversity in extant animal hosts.

Vulvovaginal candidiasis is a pervasive gynecological condition among women worldwide due to infection recurrence and resistance to conventional drugs. This calls for a novel formulation of alternative medication and with enhanced efficacy. This study aimed to fabricate mixed-lipid nanoconstructs (MLNCs) of voriconazole (VCZ) with a low concentration of lipids applying high shear homogenization and ultrasonication to form a semisolid formulation. Tefose 63 and Gelot 64 were employed as emulsifiers that are specified for vaginal preparations; as per their mucoadhesive properties and their texture enhancing characters, although usually used as lipids in different lipid carriers. A 2 4 factorial design was established and the optimized formulation was prepared using 10% total lipids, in which solid lipids (Sterotex NF: Glyceryl monostearate) ratio was 1.92:1 and the oils percentage was 30% (Maisine: Glyceryl monooleate, in the ratio of 1:1), and the emulsifiers mixture (Tefose 63: Gelot 64) ratio was 1:1, as 10% of total formulation weight. The optimized formulation with a viscosity of 964.49 ± 57.99 cp showed spherical nanoparticles (322.72 ± 15.11 nm) that entrapped 67.16 ± 3.45% of VCZ and exhibited release of 70.08 ± 2.87% in 8 h. The optimized formulation with high bioadhesive potentials significantly reduced the fungal burden in female Wistar rats infected with vaginal candidiasis, compared to the aqueous VCZ suspension ( p < .05). Furthermore, in vivo histopathological findings proved the effectiveness and the safety of the optimized MLNCs formulation after vaginal application. Inclusively, MLNCs formulation could be a promising vaginal delivery system of VCZ for the treatment of vulvovaginal candidiasis.