Targeting NAD Biosynthesis in Bacterial Pathogens: Structure-Based Development of Inhibitors of Nicotinate Mononucleotide Adenylyltransferase NadD
| Autor: | Yvonne Eyobo, Yongping Pan, Leonardo Sorci, Oleg V. Kurnasov, Nian Huang, Irina A. Rodionova, Alexander D. MacKerell, Andrei L. Osterman, Shijun Zhong, Hong Zhang |
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| Jazyk: | angličtina |
| Předmět: |
MICROBIO
PROTEINS In silico Clinical Biochemistry Biology medicine.disease_cause Crystallography X-Ray Biochemistry Article Drug Discovery medicine Escherichia coli Transferase Nicotinamide-Nucleotide Adenylyltransferase Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Pharmacology Binding Sites Nicotinamide-nucleotide adenylyltransferase Computational Biology General Medicine biology.organism_classification NAD Small molecule Bacillus anthracis Anti-Bacterial Agents Protein Structure Tertiary Kinetics Enzyme CHEMBIO chemistry Molecular Medicine NAD+ kinase |
| Zdroj: | Chemistry & Biology. (8):849-861 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2009.07.006 |
| Popis: | SummaryThe emergence of multidrug-resistant pathogens necessitates the search for new antibiotics acting on previously unexplored targets. Nicotinate mononucleotide adenylyltransferase of the NadD family, an essential enzyme of NAD biosynthesis in most bacteria, was selected as a target for structure-based inhibitor development. Using iterative in silico and in vitro screens, we identified small molecule compounds that efficiently inhibited target enzymes from Escherichia coli (ecNadD) and Bacillus anthracis (baNadD) but had no effect on functionally equivalent human enzymes. On-target antibacterial activity was demonstrated for some of the selected inhibitors. A 3D structure of baNadD was solved in complex with one of these inhibitors (3_02), providing mechanistic insights and guidelines for further improvement. Most importantly, the results of this study help validate NadD as a target for the development of antibacterial agents with potential broad-spectrum activity. |
| Databáze: | OpenAIRE |
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