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Antibiotics 2017, 6(4), 20; https://doi.org/10.3390/antibiotics6040020

Choline Kinase, A Novel Drug Target for the Inhibition of Streptococcus pneumoniae

Food Microbiology and Biotechnology Laboratory, Department of Family and Consumer Sciences, College of Agriculture and Environmental Sciences, North Carolina Agricultural and Technical University, 1601 East Market Street, Greensboro, NC 27411, USA
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Author to whom correspondence should be addressed.
Academic Editor: Leonard Amaral
Received: 28 August 2017 / Revised: 18 September 2017 / Accepted: 19 September 2017 / Published: 25 September 2017
(This article belongs to the Special Issue Top 35 of Antibiotics Travel Awards 2017)
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Abstract

Gram-positive pathogens, such as Streptococcus pneumoniae, can have deleterious effects on both human and animal health. Antibiotics and antimicrobials have been developed to treat infections caused by such pathogens and to prevent food contamination. However, these strategies have been increasingly thwarted by the emergence of resistant bacteria strains. Thus, new methods for controlling Gram-positive pathogen growth need to be continuously developed. Choline analogs, such as Hemicholinium-3 (HC-3), have been shown to be useful in blocking cell division in eukaryotic cells through the inhibition of choline kinase, an enzyme which catalyzes the production of phosphocholine from choline and ATP. In some Gram-positive pathogens, choline kinase is an important enzyme in the production of the cell wall element, lipoteichoic acid. However, it is not known if inhibiting this enzyme has any effect on cell division in Gram-positive bacteria. Using the R6 strain as a model, we tested the ability of HC-3 to block the activity of choline kinase in S. pneumoniae and inhibit cell growth. Mass-spectrometry measurements of crude extracts revealed that HC-3 blocked choline kinase activity. Turbidity measurements and population counts showed that HC-3 inhibited cell growth. Competition assays with choline suggested that HC-3 also blocked choline transporters. Western blots showed that lipoteichoic acid production was blocked in the presence of HC-3, and autolytic assays showed that this decrease in lipoteichoic acids caused cells to be more resistant to autolysis. Scanning electron microscopy revealed that HC-3 distorted the cell wall. This study thus establishes choline kinase as a novel drug target for S. pneumoniae. View Full-Text
Keywords: Streptococcus pneumonia, choline kinase, Gram-positive, lipoteichoic acid, cell wall, hemocholinium-3 Streptococcus pneumonia, choline kinase, Gram-positive, lipoteichoic acid, cell wall, hemocholinium-3
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Zimmerman, T.; Ibrahim, S. Choline Kinase, A Novel Drug Target for the Inhibition of Streptococcus pneumoniae. Antibiotics 2017, 6, 20.

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