2023 Hamilton Award: Efficient manufacture of drug candidates

Mark is a Postdoctoral Research Fellow at the School of Biological Sciences at Te Herenga Waka —Victoria University of Wellington. His research has enabled new ways to engineer microbes to produce bioactive compounds.

His breakthrough has been in the area of non-ribosomal peptide synthetases (NRPSs), found in bacteria and fungi.  Many of the antibiotics and drugs on the market are produced by NRPSs.

Peptides are short strings of amino acids, the basic building-blocks of life. In the cells of more complex organisms, such as humans, both these short peptides and the longer strings of amino acids which make up proteins are assembled by molecular machines called ribosomes. The correct sequence of amino acids for each peptide or protein is encoded in a strand of nucleic acids called messenger-RNA. Built into this system is a ‘proof-reading’ function, to ensure the linear sequence of amino acids is strung together correctly based on the sequence of nucleic acids in the messenger-RNA. 

Microbes like bacteria and fungi have evolved to make some peptides without the use of ribosomes. Instead, they use modular ‘mega-enzymes’ known as non-ribosomal peptide synthetases. Scientists have worked out a process which uses NRPS to produce useful peptides for medicine and other industries. However, it was assumed that each enzyme module would only add a particular amino acid, akin to the ‘proof-reading’ mechanism in ribosomes. 

Dr Mark Calcott and his team have overturned this assumption. They’ve shown that different forms of amino acids with different modifications, or even different amino acids can be added by a single enzyme module. This revelation has simplified the process for creating novel peptides from microbes, with each new peptide having the potential to be a useful drug.

Mark’s research has shown that “it is possible to change the amino-acid uptake of the NRPS enzyme and generate new drug analogues with different amino acids substituted,” Mark’s referee explained.

“The study… as reported in Nature Communications by Dr Calcott and his colleagues is now considered a landmark paper for NRPS engineering. It has led to a paradigm shift in the field and the approach has been subsequently proven in many leading labs in the world.”

His nominator says Mark has shown he can create modified drug candidates with unprecedented success. “His work has real potential for creating new medicines, and represents a major breakthrough in enzyme engineering and understanding the evolution of this medically-essential class of compounds.” 

His referee agrees: “Dr Calcott’s contributions to the field of NRPS engineering as an early career scientist are truly outstanding. His work will pave the way for development of new drugs, improved treatments, and better health outcomes for patients.”

On receiving this award, Mark said: “I am honoured and grateful for this incredible recognition. I would like to thank the Royal Society and my nominees for this award. I share this success with my mentors, colleagues, and loved ones who have been my pillars of strength.

“This accolade motivates me to continue pushing boundaries, fostering innovation, and making a positive impact. Thank you for believing in me and acknowledging the collective journey we've undertaken.”

Mark has been awarded a Sir Charles Hercus Health Research Fellowship (2023), a Marsden Fund Fast-Start grant(2019), and a Cancer Society research grant (2018).

Hamilton Award:
For excellent science by an early-career researcher.

Citation:
For pioneering evolutionary approaches to the engineering of microbes to enable efficient and sustainable production of new drug candidates. 

Paper details:
MJ Calcott, JG Owen, & DF Ackerley. (2020). Efficient rational modification of non-ribosomal peptides by adenylation domain substitution. Nature Communications 11: 4554. Selected as Editor’s Highlight