Journal article
From knock-out phenotype to three-dimensional structure of a promising antibiotic target from Streptococcus pneumoniae
C Dogovski, MA Gorman, NE Ketaren, J Praszkier, LM Zammit, HD Mertens, G Bryant, J Yang, MDW Griffin, FG Pearce, JA Gerrard, GB Jameson, MW Parker, RM Robins-Browne, MA Perugini
Plos One | Published : 2013
Abstract
Given the rise in drug-resistant Streptococcus pneumoniae, there is an urgent need to discover new antimicrobials targeting this pathogen and an equally urgent need to characterize new drug targets. A promising antibiotic target is dihydrodipicolinate synthase (DHDPS), which catalyzes the rate-limiting step in lysine biosynthesis. In this study, we firstly show by gene knock out studies that S. pneumoniae (sp) lacking the DHDPS gene is unable to grow unless supplemented with lysine-rich media. We subsequently set out to characterize the structure, function and stability of the enzyme drug target. Our studies show that sp-DHDPS is folded and active with a kcat = 22 s-1, KMPYR = 2.55 ± 0.05 mM..
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Awarded by National Science Foundation
Funding Acknowledgements
Funding provided by (1) Australian Research Council Future Fellowship FT0991245, (2) National Health & Medical Research Council (NHMRC) Project Grant 628681I (3) NHMRC Fellowship APP1021645. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.