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2022-06-02| R&DTechnology

Finding New Antibiotics from Bacterial Genes With Computational Biology and Genome Sequencing to Synthesize Novel Drug Molecules

by GeneOnline
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Superbugs such as Staphylococcus aureus (MRSA) and Clostridium difficile (C. difficile), are multidrug resistant, making most antibiotics ineffective, which can lead to worsening of symptoms, organ failure and death in infected patients. Since bacteria can exchange their genes with each other, causing resistance genes to circulate among the various species, superbugs have become increasingly difficult to treat. In addition, only a few new antibiotics have been introduced recently, and there are only a limited number of drugs available to combat these bacteria, representing an antibiotic crisis that cannot be ignored.

A team of researchers from Rockefeller University in New York recently published a paper in the journal Science reporting the synthesis of cilagicin, a new antibiotic molecule using analysis of bacterial genes and algorithms. It is also shown that the new drug can kill drug-resistant Gram-positive bacteria through a new mechanism.

It is interesting to note that in addition to demonstrating the clinical implications of the novel antibiotic, this study also utilized a combination of computational biology, gene sequencing and chemical synthesis to unlock the development of a novel antibiotic compound, which is expected to increase the variety of new drug candidates in the future.

Related article: First Successful Use of Phages for Treating Antibiotic-Resistant Lung Infection

 

Synthesizing New Antibiotics by Combining Algorithms With Synthetic Biology

 

Given that bacteria have evolved over billions of years to develop unique virulence patterns that compete with/kill each other, powerful antibiotics can be identified from bacteria themselves. In fact, with the exception of penicillin and other drugs derived from fungi, most antibiotics are found in the bacteria themselves.

Professor Sean F. Brady of Rockefeller University in New York has been working with a research team for over 15 years to search for the next antimicrobial gene in soil and culture it in laboratory bacteria. However, the antibiotic gene was not readily obtainable at first because it was controlled by biosynthetic gene clusters (BGCs) in the bacteria. The team then analyzed large-scale gene databases and used algorithms to assist in the analysis of DNA sequences in order to predict the types and structures of antibiotics that would be produced by bacteria containing specific sequences. Eventually, cilagicin, a novel and active antibiotic drug molecule, was successfully synthesized through organic synthesis.

Professor Brady stated that although genetic predictions by algorithms cannot be perfect, similar effects can still be achieved by synthesizing molecular structures similar to the antibiotic compounds produced by the bacteria.

According to the results of the study, cilagicin killed Gram-positive bacteria without showing human cell line cytotoxicity. Brady’s team determined that cilagicin acts by sequestering C55-P and C55-PP, two distinct, indispensable undecaprenyl phosphates used in cell wall biosynthesis. Existing antibiotics, such as bacitracin, bind one of these two molecules, but never both. Bacteria can often resist these drugs by piecing together a cell wall with the remaining molecules. They speculate that cilagicin’s ability to bind both molecules may be an insurmountable barrier to drug resistance. In addition, cilagicin has also been proven to be successful in treating bacterial infections in mice in animal studies and has shown efficacy against several drug-resistant bacteria.

Nevertheless, cilagicin still has a long way to go before it can be tested in clinical trials. In the near future, the research team intends to optimize the compound and test its efficacy against different pathogens in more animal models, with the hope that it can be applied to clinical trials soon to alleviate the drug resistance crisis.

 

Written by Aurora Mau, translated by Richard Chau

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