Biosynthesis of "non-natural" Penicillium brasilianum cyclodepsipetides: a biosynthetic engineering approach

• Grant number: 24/08254-6
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: August 23, 2024
• End date: February 22, 2025
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Taicia Pacheco Fill
• Grantee: Marina Ferreira Maximo
• Supervisor: Jason Micklefield
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: University of Manchester, England
• Associated to the scholarship: 23/01956-2 - Biosynthetic study of cyclodepsipeptides and generation of structural diversity in Penicillium brasilianum by mutational biosynthesis, BP.MS

Abstract

Fungi are huge bioactive natural product factories, as was evidenced in the 20th century with the discovery of the first antibiotics, which have revolutionised modern society. To this day, the search for new natural products is still crucial for the development of new drugs, including urgently required antibiotics and antifungals to combat pandemics and antimicrobial resistance. Advances in genetic sequencing techniques and bioinformatics indicate that the biosynthetic potential of fungi is still very little explored and there are many gene clusters responsible for the biosynthesis of specialised metabolites that have not yet been characterised. Prospecting for natural products and investigating their biosynthesis pathways can help discover new compounds and develop sustainable routes for the generation of new pharmaceutical agents. In this work, we have been investigating the biosynthesis of pipecolic acid-containing cyclodepsipeptidesproduced by the plant endophyte Penicillium brasilianum LaBioMMi-136 through the disruptionof key genes responsible for its assembly and precursors' biosynthesis. Through this, in addition to elucidating their biosynthesis, we will generate new 'non-natural' analogues of thesecyclodepsipeptides through mutational biosynthesis assays with the mutant strains. To enable ourobjectives relying on biosynthetic engineering, we will develop for the first time a new geneediting method for P. brasilianum based on CRISPR/Cas9, enhancing the genetic toolbox forthis species. This project will be supervised by Prof Dr Jason Micklefield, from the ManchesterInstitute of Biotechnology of the University of Manchester, United Kingdom.