New Drugs Block Synthesis of Metabolites by Nutrient-Challenged Bacteria

Researchers have developed a new generation of antibiotics that kill bacteria by preventing them from making critical metabolites such as vitamins and amino acids.

Characterizing new drugs has been hindered by the difficulties inherent in identifying the mechanism of action (MOA) of biologically active molecules. To attack this problem, investigators at McMaster University (Hamilton, ON, Canada) developed a metabolite suppression approach to explore the MOA of antibacterial compounds under conditions of nutrient restriction.

They assembled an array of metabolites that could be screened for suppressors of inhibitory molecules. Further, they identified inhibitors of Escherichia coli growth under nutrient limitation and charted their interactions with the metabolite array. This strategy led to the discovery and characterization of three new antibacterial compounds, MAC168425 (3-(dimethylamino)-1-(4-methoxyphenyl)propan-1-one), MAC173979 (3,3-dichloro-1-(3-nitrophenyl)prop-2-en-1-one), and MAC13772 (2-(2-nitrophenylthio)acetohydrazide). MAC168425 was found to interfere with glycine metabolism, MAC173979 was a time-dependent inhibitor of p-aminobenzoic acid biosynthesis, and MAC13772 inhibited biotin biosynthesis. These findings were published in the October 13, 2013, online edition of the journal Nature Chemical Biology.

"We have developed technology to find new antibiotics using laboratory conditions that mimic those of infection in the human body," said senior author Dr. Eric Brown, professor of biochemistry and biomedical sciences at McMaster University.

"We are taking fresh aim at bacterial vitamin and amino acid production and finding completely novel antibacterial compounds," said Dr. Brown. "We threw away chemicals that blocked growth in conventional nutrient-rich conditions and focused instead on those that were only active in nutrient-poor conditions. The approach belies conventional thinking in antibiotic research and development, where researchers typically look for chemicals that block growth in the laboratory under nutrient-rich conditions, where vitamins and amino acids are plentiful, but in the human body these substances are in surprisingly short supply and the bacteria are forced to make these and other building blocks from scratch."

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