As growing antibiotic resistance reduces the arsenal of drugs available to combat infectious diseases, the hunt is on for new chemical compounds that can be enlisted in the fight. Graduate student Gabriel Lozano (Molecular, Cellular, and Developmental Biology) and alumna Elizabeth Stulberg (PhD 2013, MCDB) recently published work that seeks to better understand the evolution of the biosynthetic pathways that lead to the production of antibiotics.
“The dearth of new antibiotics in the face of widespread antimicrobial resistance makes developing innovative strategies for discovering new antibiotics critical for the future management of infectious disease,” Lozano and Stulberg wrote.
The article, titled “Genomic and Secondary Metabolite Analyses of Streptomyces sp. 2AW Provide Insight into the Evolution of the Cycloheximide Pathway,” appears in Frontiers in Microbiology and describes the work of a team headed by Jo Handelsman, the Frederick Phineas Rose Professor of Molecular, Cellular, and Developmental Biology.
In soil from the Bonanza Creek Long-Term Ecological Research Area in Alaska, the authors found a bacterial isolate (a pure sample) that has broad antimicrobial activity. The sample came to Yale from an earlier trip taken by the Handlesman lab. Having searched in many of the world's easily accessed sites, researchers now look in places that are extremely cold, hot, wet, or dry in the hope of finding new antibiotics. When Lozano and Stulberg sequenced the soil's genome, they discovered that this new strain of Streptomyces has several putative secondary metabolite gene clusters. A bioinformatics analysis found that three of these are similar to known antibiotic biosynthetic gene clusters producing cycloheximide and two other biosynthetically unrelated, but known antibiotics. Chemical analyses confirmed that the strain produced the three compounds. Cycloheximide attracted their attention, as it belongs to a chemically diverse family of glutaramide antibiotics and thus could serve as model for studying antibiotic biosynthesis evolution.
Further work by Lozano and Stulberg allowed them to propose an evolutionary framework to explain how such chemical diversity has been generated in that family of antibiotics. This work highlights the power of modern sequencing technologies and bioinformatics, coupled with chemical analysis, to advance the understanding of antibiotic biosynthesis and the value of doing research in understudied natural environments.
The genus Streptomyces has been a source of important bioactive metabolites, including several antibiotics such as streptomycin and tetracycline, antifungal, antiparasitic, and antitumor drugs and immunosuppressants. Despite being studied for decades, scientists estimate that Streptomyces may produce up to 100,000 antimicrobial metabolites, of which only a small proportion have been identified so far. Understanding the evolution of this “diverse chemical arsenal will further enable strategies to engineer new, or as yet undiscovered, metabolic pathways and may translate to the design and production of new antibiotics in vitro,” Lozano and Stulberg suggest in the article.
Lozano grew up in Bogotá, Colombia, where he earned his undergraduate degree in chemical engineering and microbiology from Universidad de los Andes. He came to Yale in 2010 as an International Fellow of the American Society for Microbiology–Pan American Health Organization’s Infectious Diseases Epidemiology and Surveillance Fellowship to work in the Handelsman lab on the ecology and distribution of antibiotic resistance genes in the soil. After joining the PhD program, he began to explore the role of antibiotics in modulating microbe-microbe interactions within microbial communities. He maintains ties with his native country, participating in Clubes de Ciencia Colombia — an initiative that sends Colombian graduate students and post-docs in the USA and Europe back to Colombia to teach an intense, research-based, one-week course to underrepresented high school students in STEM fields.
Stulberg joined the U.S. Department of Agriculture’s Office of the Chief Scientist in 2015 as an Agriculture Science Fellow after serving as a policy analyst in the White House Office of Science and Technology Policy. Prior to that, she worked in the U.S. House of Representatives as a Science and Technology Policy Congressional Fellow. Her dissertation research on antibiotic production in soil bacteria was done in Handelsman’s laboratory. As a graduate student, Stulberg was president of the Yale Science Diplomats, a group devoted to helping the public understand the scientific underpinnings of issues in the news and encouraging scientists to become engaged in the political process. She was also a member of the Yale Belly Dance Society, an organization that brings Middle Eastern dance, music, and culture to the Yale and New Haven communities.