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December 5, 2017

Old Antibiotic Repurposed to Treat TB

D-cylcoserine phosphate in complex with ADP and magnesium bound at the active site of E. coli D-ala-D-alanine ligase.[University of Warwick]

  • Tuberculosis (TB) remains a global public health threat and a leading cause of death worldwide, therefore finding new drugs to effectively control and treat the disease is paramount. Now, new research from scientists at the University of Warwick and The Francis Crick Institute could help tackle TB and other life-threatening microbial diseases more effectively, thanks to an old antibiotic. Findings from the new study—published today in Nature Communications in an article entitled “Inhibition of D-Ala:D-Ala Ligase through a Phosphorylated Form of the Antibiotic D-Cycloserine”—may provide insight into designing new antibiotics, which are desperately needed to fight increasingly drug-resistant and deadly bacteria.

    In the new study, the investigators looked at the activity of D-cycloserine, an old antibiotic drug that is effective against many microbial diseases, such as TB, but has often been used as a second-line treatment, due to some adverse side effects.

    Interestingly, the researchers discovered that the antibiotic acts chemically in very different ways on multiple bacterial targets—possibly the only antibiotic in the world to do so. The drug attacks bacteria by inhibiting two separate enzymes (D-alanine racemase and D-alanine–D-alanine ligase) each required to build and maintain the structural integrity of bacterial cell walls. With the D-alanine racemase enzyme, it is known that the drug forms a molecular bond with a chemical group required for the enzyme activity, stopping it from working.

    "In this new discovery, we see that D-cycloserine binds to the D-alanine–D-alanine ligase enzyme and becomes chemically modified on the enzyme,” noted senior study investigator David Roper, Ph.D., professor of biochemistry and structural biology at the University Warwick. “The chemical species formed here has never been seen before. We now understand fully how this antibiotic drug can have totally different methods of working on separate targets. This appears to be a unique amongst the antibiotics."

    The researchers observed, for the first time, how D-cycloserine inhibits the D-alanine–D-alanine ligase enzyme.

    "Perhaps more important than how D-cycloserine works, this study highlights an increasingly obvious fact: We know much less than we think about how antibiotics really work and how bacteria become resistant,” explained co-senior study investigator Luiz Pedro Carvalho, Ph.D., group leader in the Mycobacterial Metabolism and Antibiotic Research Laboratory at the Francis Crick Institute. "Only by truly understanding molecular and cellular events caused by antibiotics or in response to their presence will we truly understand how to make improved drugs, which are much needed in the face of the current threat of antibiotic resistance."

    The research team noted that a long-term goal would be to modify the structure of D-cycloserine, so that it more closely resembles the newly discovered chemical species, and in so doing produce an antibiotic that is more specific and avoids some of adverse side effects of D-cycloserine—enabling its wider use in the fight against antibiotic-resistant infections.

    There is a global crisis in healthcare because bacterial infections are becoming increasingly resistant to the antibiotic drugs we use to treat them. Antimicrobial resistance threatens many aspects of human activity, including medicine and agriculture, and could lead to more deaths than cancer.

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