ONTARIO — A study published in Nature reports the discovery of a gene cluster, termed a "megacluster," that codes for four molecules working together to disrupt a single metabolic pathway. Biomedical researcher Eric Brown at McMaster University in Ontario, Canada, led the study.

The megacluster was found in Streptomyces species, which are bacteria living in soil. This gene cluster produces four molecules that target the synthesis of biotin, also known as vitamin B7. Biotin is a cofactor necessary for vital metabolic enzymes to function in many human pathogens.

Three clusters within the megacluster produce antibiotic molecules identified as stravidins, acidomycins, and dapamycins. Each of these molecules inhibits a different enzyme involved in the biotin biosynthesis pathway. The fourth cluster within the megacluster generates 2-methyl-7-keto-8-aminopelargonic acid, or α-Me-KAPA, which acts as a dummy molecule by replacing a natural biotin precursor. Additionally, the megacluster is flanked by genes that code for streptavidin, a protein known to sequester biotin.

Experiments conducted in test tubes and in mice confirmed that the products of this megacluster could kill various bacteria. These products demonstrated increased potency when utilized in combination. Steven Rutherford, a microbial sciences expert at Genentech, wrote a commentary accompanying the study.

Rutherford stated, "The discovery of a natural megacluster that encodes the production of synergistic biotin-synthesis inhibitors suggests that evolution has already identified effective combinations of antibacterials that act through distinct mechanisms." Brown said, "The architecture of the anti-biotin megacluster provides a paradigm for naturally evolved combination therapies, supporting a shift in antibiotic discovery from isolating individual hits to reconstructing native synergistic systems." More than 80 percent of antibiotics currently used in clinics are based on natural products derived from microbes, including streptomycin, an antibiotic extracted from Streptomyces species that was discovered in the 1940s.

Why It Matters

The research identifies a natural mechanism in soil bacteria that employs multiple molecules to disable a critical metabolic pathway in pathogens. This finding suggests a new approach to antibiotic development, focusing on naturally occurring combinations of antimicrobial compounds rather than single agents. The study's results, showing increased potency of these molecules when used together, could influence strategies for addressing bacterial infections.