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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).
Medical Biotechnology
Published in Firdos Alam Khan, Biotechnology Fundamentals, 2020
We will now discuss the process of generating MABs using hybridoma technology. In hybridoma technology, MABs are typically made by fusing myeloma cells with the spleen cells from a mouse that has been immunized with the desired antigen. However, recent advances have allowed the use of rabbit B-cells. Polyethylene glycol is used to fuse adjacent plasma membranes, but the success rate is low, so a selective medium is used in which only fused cells can grow. This is because myeloma cells have lost the ability to synthesize hypoxanthine-guanine-phosphoribosyl transferase (HGPRT), an enzyme necessary for the salvage synthesis of nucleic acids. The absence of HGPRT is not a problem for these cells unless the de novo purine synthesis pathway is also disrupted. By exposing cells to aminopterin, a folic acid analogue that inhibits dihydrofolate reductase (DHFR), they are unable to use the de novo pathway and become fully auxotrophic for nucleic acids, requiring supplementation to survive.
Medical biotechnology
Published in Firdos Alam Khan, Biotechnology Fundamentals, 2018
We will now discuss the process of generating MABs using hybridoma technology. In hybridoma technology, MABs are typically made by fusing myeloma cells with the spleen cells from a mouse that has been immunized with the desired antigen. However, recent advances have allowed the use of rabbit B cells. Polyethylene glycol (PEG) is used to fuse adjacent plasma membranes, but the success rate is low, so a selective medium is used in which only fused cells can grow. This is because myeloma cells have lost the ability to synthesize hypoxanthine-guanine phosphoribosyltransferase (HGPRT), an enzyme necessary for the salvage synthesis of nucleic acids. The absence of HGPRT is not a problem for these cells unless the de novo purine synthesis pathway is also disrupted. By exposing cells to aminopterin, a folic acid analogue that inhibits dihydrofolate reductase (DHFR), they are unable to use the de novo pathway and become fully auxotrophic for nucleic acids, requiring supplementation to survive.
Evaluation of anti-bacterial activity of novel 2, 3-diaminoquinoxaline derivatives: design, synthesis, biological screening, and molecular modeling studies
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Suresh Kumar Suthar, Narendra Singh Chundawat, Girdhar Pal Singh, José M. Padrón, Pavan V. Payghan, Yuvraj Kunwar Jhala
K. S. Ahmed et al. (2019) designed and synthesized novel molecules based on N3-alkyl-6-nitro-N2-benzyl quinoxaline-derivatives. The nitro-group of quinoxaline alters the DNA structure of bacterial cells and inhibits the DNA synthesis and as a result, it presented an antibacterial profiles. [66] S. Paliwal et al. (2017) designed and synthesized small drug-like novel compounds of substituted Phenyl-3-Hydrazinyl-Quinoxaline-2-amines derivatives showed potent anti-microbial activities. From docking study of compounds revealed, it binds with the specific amino acid of dihydrofolate reductase protein of Staphylococcus aureus (PDB ID-4XE6). [67] From the above research work [66,67], we have designed a novel hybride scaffold (4) in Figure 2, which have combination effect and their binding site from 1,3 nitrogen interaction of quinoxaline ring with alkyl amine and similar interaction with aromatic amine. From the reported antimicrobial activites, [66,67] similar trends has been also adopted in selected screened compounds (4b, 4c, 4 h, 4 l, 4 m, 4 n, 4 w, 4x and 4z) in scaffold (4), among them, fluorinated compound (4b, 4c, 4 h and 4 n) presented broad and moderate activity on all bacterial strains.
An exploration on the toxicity mechanisms of phytotoxins and their potential utilities
Published in Critical Reviews in Environmental Science and Technology, 2022
Huiling Chen, Harpreet Singh, Neha Bhardwaj, Sanjeev K. Bhardwaj, Madhu Khatri, Ki-Hyun Kim, Wanxi Peng
Alkaloids produce toxicity by changing enzyme activity, which affects cell physiology, DNA replication, and DNA repair. Because alkaloids can intercalate with DNA, they can affect the neuromuscular system (Yang & Stöckigt, 2010). There are around 20,000 different alkaloid molecules, and their toxicity and mode of action differ considerably with their structure. For example, pyrrolizidine alkaloids transform themselves into pyrroles to induce the alkylation of DNA and proteins. Moreover, they can induce tumors in humans, along with pulmonary abnormalities and liver damage (Moreira et al., 2018). Quinolone and iso-quinolone alkaloids inhibit cell division and DNA synthesis, whereas the indole-based alkaloids inhibit nucleic acid synthesis by affecting the activity of the dihydrofolate reductase enzyme (Cushnie et al., 2014; Shimshoni et al., 2015). Accidental ingestion of toxic alkaloids can have teratogenic effects through intoxication. Tropane alkaloids have traditionally been used for medicinal and hallucinogenic effects. However, they can also cause weakness in vision, dilation of the pupils, constipation, and poisoning (Afewerki et al., 2019). The common glycoalkaloids solanine and chaconine, isolated from Solanum spp., can cause neurological impairment by inhibiting the activity of acetyl choline neurotransmitters and Ca2+ transport across membranes (Yamashoji & Matsuda, 2013). To protect human and animal health, information about the biochemistry, toxicology, and pharmacology of plant-produced alkaloids is greatly needed.
DFT studies of temperature effect on coordination chemistry of Cu(II)-trimethoprim complexes
Published in Journal of Coordination Chemistry, 2018
Malik Zaheer Ahmed, Uzma Habib
Trimethoprim {(2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine, TMP} belongs to a synthetic antibacterial agent and diaminopyrimidine (pyridine-3,4-diamine) compound group. Dihydrofolate reductase (DHFR) is the target enzyme of trimethoprim. This enzyme catalyzes the reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate in the presence of NADPH. Trimethoprim is a good inhibitor of bacterial dihydrofolate reductase and is used to prevent the conversion of dihydrofolic acid to tetrahydrofolic acid [1, 2] (Figure 1).