5JG0
Staphylococcus aureus Dihydrofolate Reductase complexed with beta-NADPH and UCP1191
Summary for 5JG0
| Entry DOI | 10.2210/pdb5jg0/pdb |
| Descriptor | Dihydrofolate reductase, 4-{6-[(2S)-4-(2,4-diamino-6-ethylpyrimidin-5-yl)but-3-yn-2-yl]-2H-1,3-benzodioxol-4-yl}benzoic acid, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total) |
| Functional Keywords | oxidoreductase, dihydrofolate reductase, nadph, zwitterion, antibiotics |
| Biological source | Staphylococcus aureus |
| Total number of polymer chains | 1 |
| Total formula weight | 19189.42 |
| Authors | Anderson, A.C.,Reeve, S.M. (deposition date: 2016-04-19, release date: 2017-04-19, Last modification date: 2024-03-06) |
| Primary citation | Reeve, S.M.,Scocchera, E.W.,G-Dayanadan, N.,Keshipeddy, S.,Krucinska, J.,Hajian, B.,Ferreira, J.,Nailor, M.,Aeschlimann, J.,Wright, D.L.,Anderson, A.C. MRSA Isolates from United States Hospitals Carry dfrG and dfrK Resistance Genes and Succumb to Propargyl-Linked Antifolates. Cell Chem Biol, 23:1458-1467, 2016 Cited by PubMed Abstract: Antibiotic resistance is a rapidly evolving health concern that requires a sustained effort to understand mechanisms of resistance and to develop new agents that overcome those mechanisms. The dihydrofolate reductase (DHFR) inhibitor, trimethoprim (TMP), remains one of the most important orally administered antibiotics. However, resistance through chromosomal mutations and mobile, plasmid-encoded insensitive DHFRs threatens the continued use of this agent. We are pursuing the development of new propargyl-linked antifolate (PLA) DHFR inhibitors designed to evade these mechanisms. While analyzing contemporary TMP-resistant clinical isolates of methicillin-resistant and sensitive Staphylococcus aureus, we discovered two mobile resistance elements, dfrG and dfrK. This is the first identification of these resistance mechanisms in the United States. These resistant organisms were isolated from a variety of infection sites, show clonal diversity, and each contain distinct resistance genotypes for common antibiotics. Several PLAs showed significant activity against these resistant strains by direct inhibition of the TMP resistance elements. PubMed: 27939900DOI: 10.1016/j.chembiol.2016.11.007 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.879 Å) |
Structure validation
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