New tuberculosis drugs possible with understanding of old antibiotic

December 5, 2017, University of Warwick
D-cylcoserine phosphate in complex with ADP and magnesium bound at the active site of E. coli D-ala-D-alanine ligase. Credit: University of Warwick

Tuberculosis, and other life-threatening microbial diseases, could be more effectively tackled with future drugs, thanks to new research into an old antibiotic by the University of Warwick and The Francis Crick Institute.

Led by Professor David Roper at Warwick's School of Life Sciences and Dr Luiz Pedro Carvalho from The Francis Crick Institute, a paper published today in Nature Communications reveals a deeper understanding of how the antibiotic D-cycloserine uniquely works at a molecular level.

This could lead to more effective future antibiotics - which are desperately needed to fight increasingly -resistant and deadly bacteria.

D-cycloserine is an old antibiotic drug which is effective against many such as tuberculosis, but is often used as a second line treatment, because of some adverse side-effects.

The researchers have now discovered that it 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.

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

David Roper, who is Professor of Biochemistry and Structural Biology at the University Warwick, commented:

"In this new discovery, we see that D-cycloserine binds to the D-alanine-D-alanine ligase enzyme and becomes chemically modified on the . 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."

Dr Luiz Pedro Carvalho, from the Mycobacterial Metabolism and Antibiotic Research Laboratory at the Francis Crick Institute, said:

"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.

"Only by truly understanding molecular and cellular events caused by or in response to their presence will we truly understand how to make improved drugs, which are much needed in face of the current threat of ."

A longer term goal will 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 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.

The research, 'Inhibition of D-Ala:D-Ala ligase through a novel phosphorylated antibiotic', is published in Nature Communications.

Explore further: Bacteria from cystic fibrosis patient could help fight antibiotic-resistant TB

More information: Sarah Batson et al, Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine, Nature Communications (2017). DOI: 10.1038/s41467-017-02118-7

Related Stories

Bacteria from cystic fibrosis patient could help fight antibiotic-resistant TB

June 23, 2017
A newly discovered antibiotic, produced by bacteria from a cystic fibrosis patient, could be used to treat cases of drug-resistant tuberculosis (TB). This is the finding of a team of scientists from Cardiff University's School ...

Bacteria from cystic fibrosis patient could help thwart antibiotic-resistant TB

June 14, 2017
The number of drug-resistant tuberculosis (TB) cases is rising globally. But a newly discovered natural antibiotic—produced by bacteria from the lung infection in a cystic fibrosis patient—could help fight these infections. ...

Key to 'superbug' antibiotic resistance discovered

May 16, 2017
An international study led by Monash University has discovered the molecular mechanism by which the potentially deadly superbug 'Golden Staph' evades antibiotic treatment, providing the first important clues on how to counter ...

EU report: More evidence on link between antibiotic use and antibiotic resistance

July 27, 2017
The European Food Safety Authority, the European Medicines Agency and the European Centre for Disease Prevention and Control are concerned about the impact of use of antibiotics on the increase in antibiotic-resistant bacteria. ...

Recommended for you

First ancient syphilis genomes decoded

June 21, 2018
An international research team, including scientists from the Max Planck Institute for the Science of Human History, the University of Tübingen, the National School of Anthropology and History in Mexico City, and the University ...

Rhesus macaque model offers route to study Zika brain pathology

June 21, 2018
Rhesus macaque monkeys infected in utero with Zika virus develop similar brain pathology to human infants, according to a report by researchers at the California National Primate Research Center and School of Veterinary Medicine ...

California Aedes mosquitoes capable of spreading Zika

June 21, 2018
Over the last five years, Zika virus has emerged as a significant global human health threat following outbreaks in South and Central America. Now, researchers reporting in PLOS Neglected Tropical Diseases have shown that ...

Breakthrough treatment for crippling jaw disease created

June 20, 2018
A first-ever tissue implant to safely treat a common jaw defect, known as temporomandibular joint dysfunction, has been successfully tested by UCI-led researchers in a large animal model, according to new findings.

Cell-free DNA profiling informative way to monitor urinary tract infections

June 20, 2018
Using shotgun DNA sequencing, Cornell University researchers have demonstrated a new method for monitoring urinary tract infections (UTIs) that surpasses traditional methods in providing valuable information about the dynamics ...

New flu vaccine only a little better than traditional shot

June 20, 2018
A newer kind of flu vaccine only worked a little bit better in seniors this past winter than traditional shots, the government reported Wednesday.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.