Old dog, new tricks for TB antibiotic

Tuberculosis could be fought more effectively with future drugs – thanks to new research into an old antibiotic by University of Warwick and Francis Crick Institute.

Professor David Roper at Warwick’s School of Life Sciences and Dr Luiz Pedro Carvalho from The Francis Crick Institute have revealed a deeper understanding of how the antibiotic D-cycloserine uniquely works at a molecular level.

“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. The chemical species formed here has never been seen before,” said Professor Roper. “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.”

D-cycloserine is an old antibiotic drug effective against many microbial diseases 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) which are 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. A longer term goal will be to modify the structure of D-cycloserine, so that it produced an antibiotic more specific and that avoids some of adverse side effects – enabling its wider use in the fight against antibiotic resistant infections.

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 antibiotics 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 antibiotic resistance.”