GoKawiilStreptomyces bacteria make multiple antibiotics that target the production of vitamin B7.Credit: Dr Jeremy Burgess/Science Photo Library
Scientists have identified a cluster of genes in a common soil bacterium that produce a range of antibiotics that can act against multidrug-resistant bacteria. Researchers say that the discovery could lead to the development of antibiotics that are harder for pathogens to develop resistance to.
Antibiotic-resistant infections are on the rise as bacteria develop ways to get around existing drugs and are predicted to kill some 39 million people between 2025 and 2050. Antibiotics with new modes of action are desperately needed.
In a study published in Nature today1, researchers report a ‘megacluster’ of genes in Streptomyces bacteria that target a key metabolic process in bacteria. Streptomyces is one of the most studied bacterial genera and produces many antibiotic compounds, including those used to produce streptomycin, the first effective antibiotic against tuberculosis.
“They’ve discovered something new in a system so extensively studied — hidden in plain sight,” says Mark Blaskovich, who works on antibiotic development at the University of Queensland in Brisbane, Australia. The gene cluster produces five compounds — four antibiotics and a protein — that target different stages of the production of biotin, or vitamin B7, which is essential for bacterial cell growth. “Since evolution has already optimized this combination, we may be able to leverage it to develop novel antibiotic combinations,” Blaskovich says.
It is much more difficult for bacteria to develop resistance to antibiotics that attack multiple parts of an essential metabolic pathway, explains Brendan Wren, a microbiologist at the London School of Hygiene & Tropical Medicine. The latest work could also lead to the discovery of gene clusters that produce antibiotic compounds involved in other metabolic processes.
Decades-long search
Study co-author Eric Brown, a biochemist at McMaster University in Hamilton, Canada, says that he and his team had been investigating biotin metabolism as a potential target for antibiotics for decades when they discovered the mega-gene cluster. While studying stravidins, a known biotin-targeting antibiotic class, they found that the genes that encode the compounds form part of a larger set of DNA involved in biotin formation. Furthermore, that DNA encoded three other antibiotic families: acidomycin; α-Me-KAPA; and a newly discovered family of compounds called dapamycins. The gene region also contained genes for streptavidin, a protein that is known to target biotin.
The team confirmed the role of these genes by cloning a section of DNA — 65,808 base pairs long — that contained the megacluster and inserted it into a laboratory strain of Streptomyces.
“It is without precedent that we would find four biosynthetic gene clusters at a single address that make four molecules targeting the same pathway,” says Brown. The team found similar gene clusters in several Streptomyces species, suggesting that they had been conserved through evolution.