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Mechanism of Drug Resistance in Staphylococcus aureus and Future Drug Discovery
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Felipe Wakasuqui, Ana Leticia Gori Lusa, Sven Falke, Christian Betzel, Carsten Wrenger
Trimethoprim is a pyrimidine analogue that acts as an inhibitor of the dihydrofolate reductase. Sulfamethoxazole is a sulfonamide and competitive inhibitor of the dihydropteroate synthetase. Both drugs target the same metabolic pathway, disrupting folate biosynthesis, affecting the synthesis of nucleotides. They are commonly applied together, which diminishes occurrence of resistance (Wormser et al., 1982). Resistance to sulfamethoxazole is caused by mutations in the DHPS gene (Hampele et al., 1997). Two genetics mechanisms are known to confer resistance to trimethoprim, mutation in the dihydrofolate reductase gene (dfrB), and genes that encode variants of dihydrofolate reductase (i.e. dfrA, dfrG, and dfrK) (Nurjadi et al., 2014), considering the dfrG gene to be the most prevalent cause of resistance (Nurjadi et al., 2015).
Current Advances in Methane Fermentation
Published in Yoshikatsu Murooka, Tadayuki Imanaka, Recombinant Microbes for Industrial and Agricultural Applications, 2020
Toshihide Kakizono, Naomichi Nishio
Genetically marked strains are a prerequisite for genetic studies; these strains could be employed to develop a genetic-exchange system in methanogens based on an efficient selection system. Since growth of Methanobacterium thermoautotrophicum Marburg was inhibited by fluorouracil, a pyrimidine analogue, the analogue-resistant strains were isolated by spontaneous mutation. Phos-phoribosyltransferase activity in extracts of the resistant strain was one-tenth lower than in the wild-type [13]. Bacitracin-resistant mutants of M. thermoautotrophicum were also isolated spontaneously on selection plates containing the antibiotic [7]. In addition, other resistant mutants against dl-ethionine or 2-bromoethane sulfonate (a methyl coenzyme M analogue) [14], and auxotrophic mutants (l-leucine, l-phenylalanine, thiamine, adenosine [14], and formate [15]) were obtained with mutagenic treatment. Moreover, for an acetoclastic methanogen, Methanococcus voltae, several auxotrophic strains were obtained: histidine, purine, vitamin B12 [16], and coenzyme M [17].
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Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Tianmeng Sun, Yu Shrike Zhang, Pang Bo, Dong Choon Hyun, Miaoxin Yang, Younan Xia
To circumvent these hurdles, nanoparticles have been actively explored as carriers to encapsulate and deliver hydrophilic drugs. Similar to hydrophobic drugs, loading efficiency is also one of the major issues to consider because the overall dosage has to be increased when nanoparticles with low drug contents are administered [59]. Considering the hydrophobic nature of most materials used for fabricating the carriers, loading of a hydrophilic drug into such a delivery system is not always straightforward, owing to the poor miscibility between these two phases. To this end, a number of approaches have been developed to improve the loading efficiency of a hydrophilic drug. For instance, Hall and coworkers replaced 5-fluorouracil (5-FU, a hydrophilic pyrimidine analogue for cancer treatment) with 1-alkylcarbonyloxymethyl (an amphiphilic prodrug of 5-FU) to significantly increase the drug loading efficiency from 3.68% to 47.23% [60]. Fattal and coworkers discovered that adjusting the pH value of the external aqueous phase to the isoelectric point of a protein drug could increase the drug loading [61]. Xu and coworkers demonstrated that the electrostatic and hydrophobic interactions between lipidoids and a protein drug could be enhanced to facilitate the formation of protein–lipidoid complexes and thus intracellular delivery [59c]. Furthermore, McGinity and coworkers found that a less hydrophilic organic solvent in the oil phase could prevent the encapsulated hydrophilic drugs from releasing into the outer water phase [62]. For some of these modifications, the poor dispersion of a hydrophilic drug in nanoparticles, which often results in rapid release of the drug, can also be largely addressed [63].
Preparation and characterization of PLGA-PEG-PLGA polymeric nanoparticles for co-delivery of 5-Fluorouracil and Chrysin
Published in Journal of Biomaterials Science, Polymer Edition, 2020
Samira Khaledi, Sevda Jafari, Samin Hamidi, Ommoleila Molavi, Soodabeh Davaran
Cancer is the most challenging disease of the 21st century, and it takes many lives every year worldwide [1]. The standard treatments for cancer include surgery, radiotherapy, chemotherapy, immunotherapy, and some recently introduced targeted drugs [2]. Despite the development of new therapeutic strategies for cancer, chemotherapy is still considered to be the main strategy for cancer treatment [3]. Nevertheless, the clinical application of chemotherapeutic agents is limited by their toxicity and low specificity. Besides, cancer cells develop multiple drug resistance to chemotherapeutic agents resulting in the failure of treatment [4–6]. 5-Fluorouracil (5-FU) is an antineoplastic pyrimidine analogue used for treatment of multiple solid tumors [7,8]. Although 5-FU is widely used in cancer treatment, its short biological half-life and little affinity to tumor cells limit therapeutic efficacy of 5-FU. Due to this limitation, a high dose of drug is required to increase the therapeutic efficiency which in turn leads to high toxicity of the drug [9,10]. An important strategy to enhance the bioavailability of anticancer agents is the use of nano-carriers for targeted delivery of drugs to the tumor [11–14].
Trichoderma after crossing kingdoms: infections in human populations
Published in Journal of Toxicology and Environmental Health, Part B, 2023
Uener Ribeiro dos Santos, Jane Lima dos Santos
A total of 16 drugs from 5 different classes were examined in antifungal susceptibility test (AFST) using microdilution, EUCAST, CLSI and Etest® method from 1970 to 2022: allylamines (TBF), azoles (clotrimazole [CTZ], econazole [ECZ], FLC, IVZ, ITC, KTZ, MCZ, posaconazole [PSC] and VRC), echinocandins (AFG, CFG and micafungin [MFG]), pyrimidine analogue (5-FC), and polyenes (AMB and NTT). CTZ, NTT, and ECZ do not have MIC values. The therapeutic potential of each class of antifungal drug against Trichoderma are presented in Figure 6A. MFG 0.12 µg/ml (range values = 0.008–2 µg/ml) presented low MIC, whereas 5-FC 131.0 µg/ml (16.0–322.8 µg/ml) displayed the highest MIC. Approximately 56.8% (n = 104) of the isolates were tested against AMB, 51.9% against ITC (n = 95), and 49.2% against VRC (n = 90). 5-FC, FLC 86.94 µg/mL (0.12–256 µg/ml), ITC 19.73 µg/ml (0.03–256 µg/ml), and PSC 13.30 µg/ml (0.03–32 µg/ml) showed high MIC values compared to AMB, whereas the echinocandins, MFG 0.12 µg/ml (0.008–2 µg/ml), AFG 0.76 µg/ml (0.01–32 µg/ml), and CFG 1.04 µg/ml (0.01–32 µg/ml), as well as TBF had low MIC values compared to AMB (Figure 6B). 75% (12/16) of the antifungal drugs tested by AFST against Trichoderma isolates were used to treat at least one patient.