Targeting NAD biosynthesis in bacterial pathogens: Structure-based development of inhibitors of nicotinate mononucleotide adenylyltransferase NadD.
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.
Sorci
Leonardo
L
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Pan
Yongping
Y
Eyobo
Yvonne
Y
Rodionova
Irina
I
Huang
Nian
N
Kurnasov
Oleg
O
Zhong
Shijun
S
MacKerell
Alexander D
AD
Zhang
Hong
H
Osterman
Andrei L
AL
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001408:Bacillus anthracis / Q000201:enzymology; D001665:Binding Sites; D019295:Computational Biology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D007700:Kinetics; D009243:NAD / Q000096:biosynthesis* / Q000737:chemistry; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009243:NAD; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C038480:nicotinic acid mononucleotide adenylyltransferase