Benzoxazoles are frequently found as a core moiety in synthetic pharmaceuticals ranging from NSAIDs like flunoxaprofen, benoxaprofen, antibiotics like calcimycin, antibacterial like boxazomycin B, muscle relaxant like chloroxazone, to drugs used for heart diseases like tafamidis.
Although natural benzoxazoles show significant promise in pharmaceuticals, their function is impeded by the time it is taken to produce them organically and some inherently undesired properties, such as high toxicity, low potency and poor solubility. There is limited research on natural benzoxazoles, but they contain many qualities that show potential for future use in cancer, antiparasitic and antimicrobial treatments. For example, some natural benzoxazoles show promising cytotoxic activity that fights against various tumor cell lines.
Dr. Xuejun Zhu, assistant professor in the Artie McFerrin Department of Chemical Engineering at Texas A&M University, alongside students Huanrong Ouyang, Joshua Hong and Jeshua Malroy are synthesizing natural benzoxazoles using E. coli in hopes of developing a more efficient, eco-friendly and cost-effective method of producing them for future drug development.
Desiring to extract and combat certain qualities of natural benzoxazoles, the researchers turned to the microbe, E. coli—a bacterium found in the environment and within human and animal intestines, owing to its rapid growth and the ability to manipulate it genetically which is beneficial in the large-scale production.
In the study, the researchers modified an E. coli with a few essential genes for making the natural benzoxazoles by coexpressing the minimal set of enzymes required for their biosynthesis. By coupling the engineered E. coli with precursor-directed biosynthesis, a pathway is developed to produce natural benzoxazoles at a faster rate. The study found three different types of benzoxazoles could be produced simultaneously, with each type having a different biological activity such as antimicrobial, antiparasitic and anticancer.
Moreover, by coupling this E. coli-based platform with precursor-directed biosynthesis, researchers have shown that the benzoxazole biosynthetic system is highly promiscuous in incorporating fluorine, chlorine, nitrile, picolinic, and alkyne functionalities into the scaffold. By tailoring these variables, the researchers can further expand the structural diversity of benzoxazoles with the hope to reverse some of the natural benzoxazoles' inherent issues to improve solubility and potency while lowering toxicity levels.
With a sustainable way to develop natural benzoxazoles, they could potentially be used in various medications with more benefits than synthetically produced benzoxazoles. The researchers hope this is a step toward a straightforward and cost-effective method of generating novel benzoxazole analogs through protein engineering and combinatorial biosynthesis.
Reference: Huanrong Ouyang et al, An E. coli-Based Biosynthetic Platform Expands the Structural Diversity of Natural Benzoxazoles, ACS Synthetic Biology (2021).
Journal information: ACS Synthetic Biology
blog by Pravajja
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