Scientists led by Dr Luiz Pedro Carvalho at the Francis Crick Institute in London have found a promising new target in the search for new tuberculosis drugs. In the process, they say they've proven the strengths of a new research technique called metabolomics.
The researchers have demonstrated that Mycobacterium tuberculosis, the bacterium responsible for tuberculosis (TB), is destroyed by blocking a specific protein called glutamate racemase. This gives drug developers a target to set their sights on in finding new antibiotics.
TB causes the deaths of more than a million people every year and one third of the world's population is estimated to carry the infection. People who also have HIV/AIDs are especially at risk. Growing drug resistance and the need for new and better antibiotics motivated Dr Carvalho's team to look for new ways to tackle TB.
"We need to understand how existing antibiotics work to be able to design better ones," says Dr Carvalho. His team focused on an antibiotic compound known as BCDA. BCDA works against TB, but it wasn't known how.
BCDA destroys other bacteria by stopping a protein called alanine racemase from helping to build bacterial cell walls. The Crick team unexpectedly found that BCDA blocks a different protein in M. tuberculosis, one involved in building cell walls at an even earlier stage: glutamate racemase. The researchers published their findings recently in the scientific journal Antimicrobial Agents and Chemotherapy.
"BCDA will never be an anti-TB drug itself because it has other toxic effects," says Dr Carvalho. "But it has served us really well. Now we know how it works in TB, we have validated glutamate racemase as a new drug target. Researchers and the pharmaceutical industry can look for new safe compounds against it that could be developed as drugs."
It was the emerging field of metabolomics that allowed Dr Carvalho's team to learn exactly how the bacteria that cause TB are destroyed by BDCA.
Dr Carvalho says: "We know that bacteria vary in their response to antibiotics but often not how or why. This limits our ability to find new antibiotics when we're facing the challenge of increasing resistance among bacteria to our existing drugs.
"Metabolomics has huge potential to show exactly how different species of bacteria are damaged by antibiotics and so, in turn, could be used to identify new targets for drug discovery. We believe our research is the first successful application of metabolomics to identify the target of an antibacterial compound. We would never have discovered that glutamate racemase was the target of BCDA without the use of metabolomics techniques. The use of metabolomics in combination with enzymology and TB biology is almost unique to our lab."
Metabolomics uses mass spectrometry-based techniques to look at small molecules (metabolites) - the products and building blocks of biological processes - from cells and how they change over time.
Dr Carvalho explains: "The beauty and advantage over other methods is the ability to carry out the unbiased and simultaneous analysis of hundreds to thousands of metabolites, without any labelling or alteration of the molecules. You can detect how cells respond to changes in environment or how a drug works by seeing how biological processes in the cell are changed."
The research was supported by the Francis Crick Institute and by a Wellcome Trust Investigator Award.
Original research paper
Gareth A Prosser et al., Glutamate racemase is the primary target of ?-chloro-D-alanine in Mycobacterium tuberculosis, Antimicrobial Agents and Chemotherapy, doi: 10.1128/AAC.01249-16
