Sweetness is a weakness

New inhibitors may overcome bacteria’s resistance to tuberculosis drugs.

Scientists in the UK have found a way to control a key step in tuberculosis proliferation.

Mycobacterium tuberculosis is responsible for one death worldwide every 10 seconds. The bacterium responsible for tuberculosis can survive in humans for years due to protection by its cell wall and disruption of the sugar-based wall is known to kill the bacteria.

Current drugs work on this principle, but the bacteria are rapidly developing resistance to common treatments. Now, Neil Thomas and his colleagues at Nottingham and Birmingham, have designed new inhibitors of an enzyme, controlling the cell wall’s biosynthesis.

Two key enzymes are involved in cell wall synthesis; uridine diphosphate galactopyranose mutase (UDP-Galp mutase) and uridine diphosphate galactofuranosyl transferase (UDP-Galf transferase). Existing treatments disrupt UDP-Galp mutase, which halts the production of the iminosugar UDP-Galf. Thomas and his team designed a series of 1-N-imino sugars to inhibit the second enzyme, which transfers UDP-Galf onto a growing oligosaccharide chain.

The inhibitors showed moderate activity and the team hope that with further development their efficiency will improve. ’The compounds form a useful "core" which can be elaborated to make more potent compounds that are orally active’, says Thomas. However, other challenges exist. Thomas continues: ’the compounds need to be cheap to prepare, as the majority of patients are in the developing world. The challenge is to get the major pharmaceutical companies to reactivate anti-tuberculosis research, which is currently viewed as unprofitable, and to participate in clinical trials using compounds developed in universities.’

Andrew West