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Biological Chemistry

Technique finds bioactive compounds with novel mechanisms

Bacterial metabolite analysis identifies library compounds that fight tuberculosis in a new way

by Stu Borman
February 26, 2018 | APPEARED IN VOLUME 96, ISSUE 9

Drugs that employ new strategies to fight pathogens might help overcome microbial resistance to existing medications. But identifying the modes of action of new drug prospects can be difficult.

Mattia Zampieri of ETH Zurich and coworkers have now developed a metabolome profiling technique that could make this task easier and faster (Sci. Transl. Med. 2018, DOI: 10.1126/scitranslmed.aal3973).

The researchers treated Mycobacterium smegmatis, a fast-growing surrogate for M. tuberculosis, with 62 anti-TB agents with known mechanisms of action. They analyzed metabolome changes in the bacterium and identified metabolic changes characteristic of each mechanism. They then analyzed metabolic changes in the same bacterium after treatment with each of 212 GlaxoSmithKline compounds with possible anti-TB activity.

Although most of the GSK compounds were chemically distinct from classical antibiotics, the analysis indicated that most also had known mechanisms of action. But unique metabolic changes in response to 8% of the compounds suggested new mechanisms. Sequencing and proteome interaction analysis of the response of M. tuberculosis to one of those compounds confirmed that it had an unconventional mechanism—inhibition of bacterial fatty acid metabolism.

The technique may help researchers target optimal candidates for further testing in corporate compound libraries. “Knowing the mechanisms of action of compounds at an early stage of drug discovery can guide the selection of the most promising leads, even in cases where the drugs do not yet exhibit strong bactericidal or bacteriostatic effects,” the researchers note.

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