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Genome Editing, Informatics Lead to New Antibiotic

Antibiotics from engineered bacteria

Antibiotic droplets emitted from engineered bacteria (University of Warwick)

23 Oct. 2018. Researchers in the U.K. created an antibiotic acid from a natural microbe found in soil, using a combination of the genome editing technique Crispr and bioinformatics. The team from University of Warwick describe their discovery and process in the 19 October issue of the journal Chemical Science.

The Warwick researchers, led by biochemistry professors Christophe Corre and Manuela Tosin are seeking new techniques to develop useful synthetic products from natural sources, including new drugs to combat a growing resistance to current antibiotics. The antibiotic resistance problem, notes World Health Organization is global and growing. The organization says new mechanisms of resistance to antibiotics are emerging that threaten our ability to combat infections from pneumonia, tuberculosis, blood poisoning, gonorrhea, and foodborne diseases.

Corre, Tosin, and colleagues from Warwick’s synthetic biology center started with the bacterium Streptomyces sclerotialus found in soil and isolated from a sample in India. Using whole genome sequencing and other bioinformatics tools, the team discovered Streptomyces sclerotialus contains a set of 5 related genes in a pathway that could allow the pathway to produce useful natural compounds. However, the microbe has other genes that keep this pathway from functioning and, in effect, silence the genes.

The researchers used the genome editing technique known as Crispr to help solve this problem. Crispr, short for clustered regularly interspaced short palindromic repeats, is a technique for editing genomes based on bacterial defense mechanisms, where RNA identifies and monitors precise locations in DNA. The actual editing of genomes with Crispr in this and most cases today employs an enzyme known as Crispr-associated protein 9 or Cas9. RNA molecules guide the editing enzymes to specific genes needing deletion or repair.

The team used multiple rounds of Crispr editing to inactivate the bacterial genes blocking production of biochemical compounds by the microbe. With those barriers removed, the microbe began producing a number of substances, which led to development of (2-(benzoyloxy)acetyl)-L-proline that the researchers call scleric acid. To get scleric acid, however, the team needed to perform a few subsequent steps, catalyzing and condensing intermediate products.

In lab tests, the researchers found scleric acid returned mixed results against infectious bacteria. In a collection of 6 bacteria associated with antibacterial resistance known as the ESKAPE panel, the test microbes were found to resist scleric acid. However, a test with Mycobacterium tuberculosis, responsible for causing tuberculosis, provided through Eli Lilly’s open drug discovery program, scleric acid showed some effects, limiting about one-third (32%) of its growth. Further lab tests showed scleric acid also inhibited activity of a metabolic enzyme known as nicotinamide N-methyltransferase or NNMT, implicated in a number of cancers.

The authors say the study’s main contribution is the process of harnessing of bioinformatics and genome editing to break through previously difficult barriers to release new biological products. “Using synthetic biology,” notes Corre in a university statement, “our study has evidenced that breaking locks at the transcriptional level does trigger the production of truly novel bioactive substances. The next game-changer will be the successful implementation of automation and robotics to characterize the thousands of natural products that remain encrypted at the DNA level.”

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