The discovery of “megacluster” antibiotics offers a new way to fight superbugs

It’s an “exciting advance in trying to reverse engineer weapons,” Steven Rutherford, a microbiologist at Genentech, wrote in a commentary accompanying Nature. “Furthermore, this study provides a road map showing how genome mining can be used to identify new natural antibacterial agents and methods of use.”

The mechanism by which megacluster drugs attack is one that produces biotin, also known as vitamin B7. The plant is required for the growth and destruction of many human pathogens, and, in particular, it is a cofactor that essential enzymes need to function properly. Some bacteria can degrade biotin in their environment, but it is usually to a small extent, and the bacteria have protective mechanisms to make it themselves.

Brown and co-workers made the exciting discovery of a biotin megacluster Streptomyces species, which are best studied. Streptomyces are bacteria that live in the soil and are known as gold mines for identifying antibiotic molecules. Many natural substances have already been extracted from the oil, including the antibiotic streptomycin, an important drug discovered in the 1940s. Despite this, the megacluster has been overlooked until now, perhaps in part because bacteria in the lab are often grown in nutrient-rich media.

A new way

Also, when researchers search for new antibiotics in bacterial genomes, they analyze the biosynthetic gene groups (BGCs) that may be responsible for making individual molecules. But Brown’s team discovered a cluster of four – a megacluster – that produces not just one molecule, but four that work in different ways to step up the biotin pathway. Careful research has shown that three clusters produce antibiotic-resistant molecules – stravidins, acidomycins, dapamycins – that inhibit a different enzyme in the biotin biosynthesis pathway. The remaining fourth group forms 2-methyl-7-keto-8-aminopelargonic acid, or α-Me-KAPA, which appears to be a dummy molecule that takes the place of the biotin precursor, essentially hijacking the process to give a useless biotin-like form.