Cycling down the RiPP pathway: biosynthesis and properties of new thiopeptide antibiotics

GHILAROV_J23DTP

Natural products from bacteria form the basis of the modern medicine. However, we are fast running out of antibiotics due to the problem of antimicrobial resistance (AMR). In recent years thousands of new natural products were bioinformatically predicted, belonging to the group of RiPPs – ribosomally-synthesized post-translationally modified peptides. These are made as precursor peptides by the ribosome and later enzymatically converted into chemically diverse bioactive molecules.

We are investigating the functions of one group of RiPP modification enzymes called YcaO. YcaOs activate peptide bonds using ATP to introduce azole rings, thioamides or amidine links into peptides resulting in a wide array of different compounds including antibiotics thiopeptides. Harnessing the ability of YcaOs to modify bespoke peptides will be of huge advantage to biotechnology and medicine.

In this project, the student will characterise a new predicted thiopeptide system featuring multiple YcaO enzymes. They will produce antibiotics encoded by these clusters, using both native and heterologous expression systems, and investigate the biochemistry of their biosynthesis.
As RiPP modification enzymes assemble into multi-protein complexes, cryo-EM is the method of choice to get insights about their structure, organisation and function.

The student will work together with national and international collaborators under the supervision of the PI and a postdoctoral researcher in a Wellcome-funded newly established and dynamic group, and will have an opportunity to learn a plethora of modern research methods including structural biology, mass-spectrometry, molecular biology, different expression systems, natural product purification, NMR and biophysical techniques.

The successful candidate will have access to the state of the art research facilities at the JIC as well as a friendly and stimulating research and training environment.
They will be part of a highly interdisciplinary team focussed on antibiotic discovery and supported in acquiring transferable skills such as written and spoken communication, mentoring and leadership.

References

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