Targeting NAD Biosynthesis in Bacterial Pathogens: Structure-Based Development of Inhibitors of Nicotinate Mononucleotide Adenylyltransferase NadD

Leonardo Sorci, Yongping Pan, Yvonne Eyobo, Irina Rodionova, Nian Huang, Oleg Kurnasov, Shijun Zhong, Alexander D. MacKerell, Hong Zhang, Andrei L. Osterman

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The 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.

Original languageEnglish (US)
Pages (from-to)849-861
Number of pages13
JournalChemistry and Biology
Volume16
Issue number8
DOIs
StatePublished - Aug 28 2009

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Bacterial Structures
Biosynthesis
Pathogens
NAD
Enzymes
Anti-Bacterial Agents
Bacillus anthracis
Bacilli
Escherichia coli
Bacteria
Guidelines
Molecules
nicotinic acid mononucleotide adenylyltransferase

Keywords

  • CHEMBIO
  • MICROBIO
  • PROTEINS

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Molecular Biology
  • Clinical Biochemistry
  • Molecular Medicine
  • Pharmacology

Cite this

Targeting NAD Biosynthesis in Bacterial Pathogens : Structure-Based Development of Inhibitors of Nicotinate Mononucleotide Adenylyltransferase NadD. / Sorci, Leonardo; Pan, Yongping; Eyobo, Yvonne; Rodionova, Irina; Huang, Nian; Kurnasov, Oleg; Zhong, Shijun; MacKerell, Alexander D.; Zhang, Hong; Osterman, Andrei L.

In: Chemistry and Biology, Vol. 16, No. 8, 28.08.2009, p. 849-861.

Research output: Contribution to journalArticle

Sorci, L, Pan, Y, Eyobo, Y, Rodionova, I, Huang, N, Kurnasov, O, Zhong, S, MacKerell, AD, Zhang, H & Osterman, AL 2009, 'Targeting NAD Biosynthesis in Bacterial Pathogens: Structure-Based Development of Inhibitors of Nicotinate Mononucleotide Adenylyltransferase NadD', Chemistry and Biology, vol. 16, no. 8, pp. 849-861. https://doi.org/10.1016/j.chembiol.2009.07.006
Sorci, Leonardo ; Pan, Yongping ; Eyobo, Yvonne ; Rodionova, Irina ; Huang, Nian ; Kurnasov, Oleg ; Zhong, Shijun ; MacKerell, Alexander D. ; Zhang, Hong ; Osterman, Andrei L. / Targeting NAD Biosynthesis in Bacterial Pathogens : Structure-Based Development of Inhibitors of Nicotinate Mononucleotide Adenylyltransferase NadD. In: Chemistry and Biology. 2009 ; Vol. 16, No. 8. pp. 849-861.
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