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Genetic and Chemical Screening in Human Blood Serum Reveals Unique Antibacterial Targets and Compounds Against Klebsiella pneumoniae

69 Pages Posted: 31 Jan 2020 Publication Status: Published

See all articles by Brent S. Weber

Brent S. Weber

McMaster University - Department of Biochemistry and Biomedical Sciences

Aaron M. De Jong

McMaster University - Department of Biochemistry and Biomedical Sciences

Amelia B.Y. Guo

McMaster University - Department of Biochemistry and Biomedical Sciences

Srinivas Dharavath

McMaster University - Department of Biochemistry and Biomedical Sciences

Shawn French

McMaster University - Department of Biochemistry and Biomedical Sciences

Aline A. Fiebig-Comyn

McMaster University - Department of Biochemistry and Biomedical Sciences

Brian K. Coombes

McMaster University - Department of Biochemistry and Biomedical Sciences

Jakob Magolan

McMaster University - Department of Biochemistry and Biomedical Sciences

Eric D. Brown

McMaster University - Department of Biochemistry and Biomedical Sciences

More...

Abstract

Antibiotics halt the growth of bacteria in the laboratory by targeting core, essential physiology that is required for life on standard microbiological media. Many more biochemical and virulence processes, however, are required for bacteria to cause infection in a host. Indeed, chemical inhibitors of the latter processes are overlooked using conventional antibiotic drug discovery approaches. Here, we use human blood serum as an alternative growth medium to explore new targets and compounds. High-throughput screening of genetic and chemical libraries identified compounds targeting biological activities required by Klebsiella pneumoniae to grow in serum, such as nucleobase biosynthesis and iron acquisition, and showed that serum can chemically transform compounds to reveal cryptic antibacterial activity. One of these compounds, ruthenium red, was effective in a rat bloodstream infection model. Our data demonstrate that human serum is an effective tool to find new chemical matter to address the current antibiotic resistance crisis.

Keywords: antibiotics, high-throughput screening, antibacterial, Klebsiella pneumoniae, bacterial pathogen, blood serum, serum

Suggested Citation

Weber, Brent S. and De Jong, Aaron M. and Guo, Amelia B.Y. and Dharavath, Srinivas and French, Shawn and Fiebig-Comyn, Aline A. and Coombes, Brian K. and Magolan, Jakob and Brown, Eric D., Genetic and Chemical Screening in Human Blood Serum Reveals Unique Antibacterial Targets and Compounds Against Klebsiella pneumoniae. Available at SSRN: https://ssrn.com/abstract=3526892 or http://dx.doi.org/10.2139/ssrn.3526892
This version of the paper has not been formally peer reviewed.

Brent S. Weber

McMaster University - Department of Biochemistry and Biomedical Sciences

Canada

Aaron M. De Jong

McMaster University - Department of Biochemistry and Biomedical Sciences

Canada

Amelia B.Y. Guo

McMaster University - Department of Biochemistry and Biomedical Sciences ( email )

Canada

Srinivas Dharavath

McMaster University - Department of Biochemistry and Biomedical Sciences

Canada

Shawn French

McMaster University - Department of Biochemistry and Biomedical Sciences

Canada

Aline A. Fiebig-Comyn

McMaster University - Department of Biochemistry and Biomedical Sciences

Canada

Brian K. Coombes

McMaster University - Department of Biochemistry and Biomedical Sciences

Canada

Jakob Magolan

McMaster University - Department of Biochemistry and Biomedical Sciences

Canada

Eric D. Brown (Contact Author)

McMaster University - Department of Biochemistry and Biomedical Sciences ( email )

Canada

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