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Flucytosine (5-Fluorocytosine; 5-FC)
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Flucytosine is metabolized via the pyrimidine salvage pathway, where it acts as a subversive substrate. Metabolism produces toxic nucleotides that interfere with nucleic acid and protein synthesis. Flucytosine is transported into fungi by membrane permeases, where it is deaminated by the protein cytosine deaminase to produce 5-fluorouracil (5-FU). 5-FU is then converted to 5-fluoro-uridylate (5-fluoro-UMP; 5-FUMP) by the protein uracil phosphoribosyltransferase (UPRT). 5-FUMP is sequentially phosphorylated to form 5-fluoro-UTP, which is incorporated into RNA. 5-FUMP is also reduced to 5-fluoro-2′-doexyuridy-late, which inhibits the enzyme thymidylate synthetase. This leads to reduced DNA synthesis because of a reduction in the available nucleotide pool. The differential activity of flucytosine is due to the absence of cytosine deaminase in mammalian cells.
Arcobacter
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Nuria Salas-Massó, Alba Perez-Cataluña, Luis Collado, Arturo Levican, Maria José Figueras
In relation with molecular mechanisms of antibiotic resistance, two independent studies (carried out in France and Belgium) have assessed the presence of potential mutations in the quinolone resistance determining region (QRDR) of gyrA gene in ciprofloxacin-resistant clinical strains [116,117]. Both studies found similar results, in the French study two A. butzleri and one A. cryaerophilus strains harbored a cytosine-to-thymine transition in position 254 of the gyrA gene, resulting in the amino acid substitution Thr-85-Ile in the GyrA protein [117], while in the Belgian study 10 Arcobacter strains showed the same point mutation [116]. So far, there are no other studies investigating the resistance mechanisms in Arcobacter. However, the genome of A. butzleri (RM 4018 strain) has some putative resistance genes, such as (1) the cat gene related to chloramphenicol resistance because it encodes a chloramphenicol O-acetyltransferase; (2) three putative β-lactamase genes (AB0578, AB1306, and AB1486); and (3) the lrgAB operon, which is associated with β-lactam resistance [29]. However, the upp gene, encoding uracil phosphoribosyltransferase, associated with 5-fluorouracil resistance, was not detected in the A. butzleri genome. The genomic analysis of an A. cryaerophilus strain detected in sewage was published [118], and the authors highlight the capacity of this bacterium to accumulate a large number of antibiotic resistance genes (ARGs). It was observed that 5% of open reading frames (ORFs) encoded ARGs belonging to 25 categories, being macrolides, fluoroquinolones, aminocoumarin, and vancomycin resistance genes the most abundant groups [118]. Considering the availability of at least 46 draft genomes of Arcobacter spp., it would be interesting to screen them for the presence of those and other potential resistance genes in the near future.
Antifungal drug resistance: Significance and mechanisms
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Sharvari Dharmaiah, Rania A. Sherif, Pranab K. Mukherjee
Mechanism of flucytosine resistance in fungal cells is well documented and is commonly mediated by modification in cytosine permease and ribosyl transferase activities [193–196]. Additional mechanisms include failure to metabolize flucytosine to 5FUTP and 5FdUMP, or from the loss of feedback control of pyrimidine biosynthesis [134,197]. The homozygous resistant strain fcy1/fcy1 (lacking functional UMP pyrophosphorylase) was associated with decreased UMP pyrophosphorylase activity that resulted in poor conversion from 5-flucytosine to FUMP, whereas resistance in fcy2/fcy2 strains was associated with decreased cytosine deaminase activity [198,199]. Hope et al. [196] evaluated flucytosine resistance mechanisms in 25 C. albicans strains by identifying and sequencing the genes FCA1 (encoding cytosine deaminase), FUR1 (encoding uracil phosphoribosyltransferase; UPRT), FCY21 and FCY22 (encoding two purine-cytosine permeases). These investigators showed an association between a polymorphic nucleotide and resistance to flucytosine within FUR1 (with a C301T nucleotide substitution), which resulted in R101C substitution in UPRT. A single resistant isolate, lacking this FUR1 polymorphism, contained instead a homozygous polymorphism in FCA1 that resulted in a G28N substitution in cytosine deaminase. Single nucleotide polymorphism has also been linked to clade-specific resistance in C. albicans clades. In this regard, Dodgson et al. [200] evaluated flucytosine resistance patterns in C. albicans clades and showed that a single nucleotide change (C301T) in FUR1 can lead to flucytosine resistance in clade I isolates. The flucytosine MICs for strains with no copies, one copy, and two copies of the mutant allele were ≤0.25 µg/mL, >0.5 µg/mL, and >16 µg/mL, respectively. Vlanti and Diallinas [201] recently cloned and characterized the A. nidulans fcyB, encoding the closest homologue to the yeast Fcy2p/Fcy21p permeases. A fcyB null mutant lacked all known purine transporters and was resistant to flucytosine. These investigators showed FcyBp to be a low-capacity, high-affinity, cytosine-purine transporter, with scavenging of cytosine-purine as its main function. In a recent study, Papon et al. [202] showed that inactivation of the FCY2, FCY1, and FUR1 genes in C. lusitaniae produced two patterns of resistance to flucytosine. Mutant fur1 demonstrated resistance to 5-fluorouracil, whereas mutants fcy1 and fcy2 demonstrated fluconazole resistance in the presence of sub-inhibitory flucytosine concentrations.
Porphyromonas gingivalis diffusible signaling molecules enhance Fusobacterium nucleatum biofilm formation via gene expression modulation
Published in Journal of Oral Microbiology, 2023
Yukiko Yamaguchi-Kuroda, Yuichiro Kikuchi, Eitoyo Kokubu, Kazuyuki Ishihara
Eighty-seven genes were downregulated (Table 2), including those encoding protein involved in de novo synthesis of purine (phosphoribosyl amine-glucine ligase, purH, class I SAM-dependent methyltransferase, phosphoribosyl glycinamide formyl transferase, purM, amidophosphoribosyltransferase, phosphoribosylaminoimidazole-succinocarboxamide synthase, purE, and phosphoribosylformylglycinamidine synthetase), proteins involved in de novo pyrimidine synthesis (bifunctional pyr operon transcriptional regulator/uracil phosphoribosyltransferase PyrR, aspartate carbamoyltransferase, dihydroorotase, glutamine-hydrolyzing carbamoyl-phosphate synthase small subunit, carbamoyl-phosphate synthase large subunit, dihydroorotate dehydrogenase electron transfer subunit, dihydroorotate dehydrogenase, orotidine 5’-phosphate decarboxylase, and orotate phosphoribosyltransferase), bioA involved in biotin metabolism, and TonB-dependent receptor.
Promising RNA-based cancer gene therapy using extracellular vesicles for drug delivery
Published in Expert Opinion on Biological Therapy, 2020
Vivian Weiwen Xue, Sze Chuen Cesar Wong, Guoqi Song, William Chi Shing Cho
Structural modification and membrane encapsulation are two common strategies used to enhance therapeutic mRNA stability and ensure mRNA translational efficiency in cancer gene therapy. Based on a previous study, 5ʹ and 3ʹ UTR sequences from human β-globin could be used to decorate therapeutic mRNA and prolong its half-life in systemic administration, and this modification did not increase immune responses [67]. Loading therapeutic mRNA as EV cargos by transfection is another choice of delivery for mRNA supplementary. Mizark et al. reported that MVs secreted from engineered cells that have the additional expression of fused cytosine deaminase (CD) and uracil phosphoribosyltransferase (UPRT) inhibited the tumor growth in xenografted mice with human schwannoma [68]. Similarly, CD-UPRT-enriched EVs also showed treatment effects in glioblastoma, which inhibited tumor growth in about 70% efficiency [69]. This is not the only example of EV-mediated mRNA therapeutics for cancer treatment. Engineered MSC-derived exosomes provide an alternative tool to deliver suicide mRNA for targeted cancer gene therapy. Altanerova et al. applied dental pulp MSCs-derived exosomes to transfer yCD-UPRT therapeutic mRNA, and this treatment resulted in significant death of tumor cells while inhibiting tumor growth in glioblastoma [70]. In the following study, they continuously reported that exosomes with yCD-UPRT released by many types of MSCs have tumor-killing effects in many types of cancers including prostate cancer and breast cancer. Moreover, miRNA cargos of exosomes do not affect cancer treatment [71]. The tumor-killing mechanism of CD-UPRT and yCD-URRT therapeutic mRNA depends on the conversion from nontoxic 5-FC to 5-FU that has strong cytotoxicity [68–71]. Other suicide gene systems such as HSV-tk/GCV may also be developed as a cancer gene therapy, and the potential of these therapeutic mRNA still needs further explorations [72]. It is worth noting that the efficiency of mRNA loading into EVs is related to the length of RNA molecules [73], which we should pay attention to when designing the therapeutic mRNA.
Toxicity, preparation methods and applications of silver nanoparticles: an update
Published in Toxicology Mechanisms and Methods, 2022
Anuj Choudhary, Sanjiv Singh, V. Ravichandiran
One study examined the chemical process of silver nanoparticles and revealed that planned cell death was directly proportional to amount in certain conditions. They also discovered a combining impact on cell death utilizing uracil phosphoribosyltransferase -expressing cells and non-UPRT-expressing cells in the presence of 5-FU (Gopinath et al. 2008). They observed that silver nanoparticles not only induce apoptosis, but also sensitize cancer cells in these conditions. Metallothionein upregulation, downregulation of key actin-binding protein, filamin, and mitotic arrest were all seen in silver nanoparticles -treated cells (AshaRani et al. 2009). The shape of cancer cells implies that biologically produced silver nanoparticles might dramatically trigger cell death. In human breast cancer MDA-MB-231 cells, anticancer properties of bacterial (B-silver nanoparticles) and fungal extract-produced silver nanoparticles (F-silver nanoparticles) were revealed. Both biologically generated silver nanoparticles were highly cytotoxic (Gurunathan, Han, Dayem, et al. 2013; Gurunathan, Han, Eppakayala, et al. 2013). Because of the kind of reducing agents utilized in the production of silver nanoparticles, fungal extract-derived silver nanoparticles exhibited a greater impact than B-silver nanoparticles. silver nanoparticles derived from Escherichia fergusoni were likewise shown to be cytotoxic to MCF-7 cells in a dose-dependent manner (Gurunathan, Han, Dayem, et al. 2013). Investigator examined the cellular and molecular mechanisms of nanoparticle-induced effects using normal human lung cells IMR-90 and human brain cancer cells U251. They discovered that silver nanoparticles may adsorb cytosolic proteins on their surface, which can impact the activity of intracellular molecules, as well as control gene expression and pro-inflammatory cytokines (AshaRani et al. 2012). According to the study findings researcher used microarray analysis to investigate the intriguing cellular transcriptome profiling after interaction to the human lung epithelial cell line A549. Silver nanoparticles have the ability to change the regulatory of over 1000 genes (Foldbjerg et al. 2012). The nanoparticles are more capable of destroying cancerous cells than non-cancerous cells at low irradiation power density. Investigator developed a sensitive and specific detection aptamer-based Ag–Au shell–core nanostructure-photothermal treatment in which the nanostructures targeted cells with great affinities and accuracy (Wu et al. 2013). In C6 glioma-bearing rats, intratumoral injection of silver nanoparticles in combination with a single dose of ionizing radiation increased therapeutic effectiveness (Liu et al. 2013).