9AUY
Crystal structure of S. aureus GuaB dCBS with inhibitor GNE9123
Summary for 9AUY
| Entry DOI | 10.2210/pdb9auy/pdb |
| Descriptor | Inosine-5'-monophosphate dehydrogenase, INOSINIC ACID, N-(6-chloropyridin-3-yl)-N~2~-(1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)-L-alaninamide, ... (4 entities in total) |
| Functional Keywords | guab, inhibitor, oxidoreductase |
| Biological source | Staphylococcus aureus More |
| Total number of polymer chains | 1 |
| Total formula weight | 41329.18 |
| Authors | |
| Primary citation | Kofoed, E.M.,Aliagas, I.,Crawford, T.,Mao, J.,Harris, S.F.,Xu, M.,Wang, S.,Wu, P.,Ma, F.,Clark, K.,Sims, J.,Xu, Y.,Peng, Y.,Skippington, E.,Yang, Y.,Reeder, J.,Ubhayakar, S.,Baumgardner, M.,Yan, Z.,Chen, J.,Park, S.,Zhang, H.,Yen, C.-W.,Lorenzo, M.,Skelton, N.,Liang, X.,Chen, L.,Hoag, B.,Li, C.S.,Liu, Z.,Wai, J.,Liu, X.,Liang, J.,Tan, M.W. Discovery of GuaB inhibitors with efficacy against Acinetobacter baumannii infection. Mbio, 15:e0089724-e0089724, 2024 Cited by PubMed Abstract: Guanine nucleotides are required for growth and viability of cells due to their structural role in DNA and RNA, and their regulatory roles in translation, signal transduction, and cell division. The natural antibiotic mycophenolic acid (MPA) targets the rate-limiting step in guanine nucleotide biosynthesis executed by inosine-5´-monophosphate dehydrogenase (IMPDH). MPA is used clinically as an immunosuppressant, but whether inhibition of bacterial IMPDH (GuaB) is a valid antibacterial strategy is controversial. Here, we describe the discovery of extremely potent small molecule GuaB inhibitors (GuaBi) specific to pathogenic bacteria with a low frequency of on-target spontaneous resistance and bactericidal efficacy against mouse models of infection. The spectrum of GuaBi activity includes multidrug-resistant pathogens that are a critical priority of new antibiotic development. Co-crystal structures of , and GuaB proteins bound to inhibitors show comparable binding modes of GuaBi across species and identifies key binding site residues that are predictive of whole-cell activity across both Gram-positive and Gram-negative clades of Bacteria. The clear efficacy of these small molecule GuaB inhibitors in a model of infection validates GuaB as an essential antibiotic target. PubMed: 39207111DOI: 10.1128/mbio.00897-24 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.94 Å) |
Structure validation
Download full validation report
