Wednesday, 07 December 2016 11:56

Unlocking cryptic Streptomyces genes in the search for potential new antibiotics

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Published in mBiosphere
Lincomycin-sensitive (L) and -resistant (R) S. coelicolor Lincomycin-sensitive (L) and -resistant (R) S. coelicolor

Actinobacteria are the bacterial phylum responsible for production of many clinically-relevant antibacterial compounds. Streptomyces is a soil-dwelling genus of actinobacteria that produces drugs like neomycin and chloramphenicol. Despite deriving many antibiotics already from Streptomyces, could there be still-undiscovered compounds made by these bacteria to increase our antimicrobial arsenal? Finding and characterizing these ‘cryptic’ pathways is the basis for a new study published in Antimicrobial Agents and Chemotherapy.

Click to read the study

Previous genome manipulation of S. coelicolor had led to increased production of certain antibiotics. Antibiotic production was particularly enhanced by mutations that affected the ribosome, which is why the researchers looked chose lincomycin to study: lincomycin inhibits bacterial ribosome function, and therefore may serve as a substitute for studying ribosomal mutations. In this report, a scientific team led by Guojun Wang and Kozo Ochi, compared the genome sequences of lincomycin-sensitive and -resistant S. coelicolor to identify mutations that may affect production of other antibiotics.

The differences in genome sequences revealed a novel mutation, which was an in-frame DNA deletion in two S. coelicolor genes, SCO4597 and SCO4598. The mutation caused the two to fuse in an in-frame hybrid gene called linR (for lincomycin resistance). When the team deleted linR, the S. coelicolor strain returned to a lincomycin-sensitive state; resistance conferred to linR-expressing Escherichia coli further confirmed the role of linR in lincomycin resistance.

Expression of actinorhodin genes increases in the linR mutantExpression of actinorhodin genes increases in the linR lincomycin-resistant mutant strain. Source

The linR mutation not only increases resistance to lincomycin, but leads to increased expression of a different antibiotic, actinorhodin (see figure, right). Actinorhodin is a polyketide antibiotic, a class made of secondary metabolites that include a number of antibiotics. How does a mutation that leads to resistance to one antibiotic increase production of another?

To answer that question, we have to understand a bit more about the genes involved. The linR gene product is the fusion of two sensor histidine kinases in a two-component network, both which interact with response regulator SCO4596 as part of a dual two-component system. The fusion to a single histidine kinase renders the LinR-SCO4596 a standard two-component system. The dual two-component system is established to regulate actinorhodin expression, but the fusion of LinR changes the signaling system in a yet-undefined way. The authors speculate that an overactive LinR enzyme may both increase lincomycin resistance and actinorhodin overproduction, but this hypothesis will need to be tested in future studies to reveal the exact mechanism.

The exciting finding of this study is the increase in one secondary metabolite production in a strain resistant to another. Genome analyses suggest there may be uncharacterized S. coelicolor pathways yet to identify various secondary metabolites that may serve as future antibiotics: at least 22 have been identified as “probable” secondary metabolites in the lab-standard S. coelicolor A3 strain. Finding conditions that increase production of these cryptic secondary metabolites, such as the linR mutation, will allow scientists to concentrate and study the potential of these compounds to aid in fighting microbial infections. 

Last modified on Wednesday, 14 December 2016 14:43
Julie Wolf

Julie Wolf is the ASM Science Communications Specialist. She contributes to the ASM social media and blog network and hosts the Meet the Microbiologist podcast. She also runs workshops at ASM conferences to help scientists improve their own communication skills. Follow Julie on Twitter for more ASM and microbiology highlights at @JulieMarieWolf.

Julie earned her Ph.D. from the University of Minnesota, focusing on medical mycology and infectious disease. Outside of her work at ASM, she maintains a strong commitment to scientific education and teaches molecular biology at the community biolab, Genspace. She lives in beautiful New York City.