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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).
Uptake, translocation, and metabolism of sulfamethazine by Arabidopsis thaliana: distinguishing between phytometabolites and abiotic transformation products in the media
Published in International Journal of Phytoremediation, 2020
As structural analogs to p-aminobenzoic acid, sulfonamides act as competitive substrates for dihydropteroate synthase, thereby impairing folate synthesis and forming pterin-sulfonamide conjugates (Zhang et al.2012). Conjugation of sulfonamides with pterin has been observed in microorganisms (Achermann et al.2018), phytoplankton (Stravs et al.2017), and A. thaliana (Huynh and Reinhold 2019). Formation of pterin-SMT in A. thaliana plant tissues potentially reduced the plant folate pool size, as previously reported (Zhang et al.2012). Based on the detection of pterin-SMT only in planted reactors (Figure 2), formation of the pterin-SMT conjugate was attributed to phytometabolism.
Novel oxazolidinone zinc(II) complexes as antibacterial and anti-SARS-CoV-2 agents: synthesis, characterization, DFT calculations, ADMET, in silico molecular docking and biological activities
Published in Journal of Coordination Chemistry, 2023
Hadjer Merazka, Afaf Bouchoucha, Mounir Nessaib, Nadjia Bensouilah, Karima Si Larbi, Amal Bouzaheur, Meziane Brahimi
Molecular docking simulation was performed to investigate the inhibition of dihydropteroate synthase (DHPS) of three infectious bacteria, Escherichia coli (PDB ID:1AJ0), Staphylococcus aureus (PDB ID: 1AD4), and Streptococcus pneumoniae (PDB ID: 2VEG) and ribosome 50S subunit from Haloarcula marismortui (PDB ID: 3CPW) by the oxazolidinone derivative ligands and Zn(II) complexes. The best conformations were selected according to the binding affinity and hydrogen bond interactions.
Docking assisted DNA-binding, biological screening, and nuclease activity of copper complexes derived from sulfonamides
Published in Journal of Coordination Chemistry, 2021
Arusa Akhtar, Muhammad Danish, Awais Asif, Muhammad Nadeem Arshad, Abdullah M. Asiri
Sulfa drugs have been used against many life-threatening microorganisms, such as gram-positive and gram-negative bacteria [33]. They inhibited the synthesis of folate by binding with specific enzyme dihydropteroate synthase (DHPS). Due to this mechanism, cell division is eventually stopped, and it depends on the concentration of sulfonamides varying between few milligrams to 100 mg [34]. Eldesouky et al. proved that these antibacterial sulfonamides also act as antifungal compounds by inhibited fungal folate pathway [35]. Fungal species are responsible for Mycoses infection that may vary from superficial mycoses to muscles, internal system infections. Under specific conditions, some fungal infections can be lethal, such as histoplasmosis, aspergillosis, blastomycosis, candidiasis, and coccidioidomycosis [36]. Also, Cu(II) complexes of sulfonamides are investigated as antioxidants, which are capable of scavenging free radicals through a variety of mechanisms and maintain biological cellular components, such as proteins and DNA [37]. Cu(II) complexes of sulfonamides have also shown tremendous enzyme inhibition activities [38]. Enzymes are naturally occurring biomolecules that act as a catalyst to regulate the metabolic activity in the living system. Any disorder in these activities causes serious diseases, such as Alzheimer’s disease, joints associated diseases, tumor growth, and lung diseases [39]. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes metabolically deteriorate the acetylcholine. Acetylcholine is a neurotransmitter that activates muscarinic and nicotinic receptors [40]. So, AChE inhibitors are administered to increase the level of acetylcholine that reduces the chances of Alzheimer’s disease [41–45]. Keeping in view the importance of sulfonamides, in this study, we have synthesized a series of copper complexes bearing sulfonamide moiety. Further, the structural and biological analysis of these compounds has been elaborated by different experimental and theoretical methods.