News / 9 September 2019

Glycopeptide antibiotics such as vancomycin and teicoplanin are last-resort drugs used to counter life-threatening multi-drug resistant bacteria. Understanding the peptide machinery involved in the biosynthesis that produces them is vital to re-engineering them and producing new antibiotics to fight ever-changing multi-resistant strains.

EMBL Australia Group Leader Associate Professor Max Cryle, and researchers from the Monash Biomedicine Discovery Institute (BDI) have revealed a novel mechanism in glycopeptide antibiotics (GPA) biosynthesis that may help in the development of new antibiotics.

Their findings were published in Chemical Science.

Peptide heptapeptide sequences are the backbone of GPAs. In order to alter these sequences and create new antibiotics researchers need to re-engineer biosynthesis pathways to enable the production of modified compounds. But before doing that it is crucial to understand how current antibiotics are biosynthesised.

“What we found was that in order to enable effective peptide biosynthesis by non-ribosomal peptide synthetase (NRPS) machinery, a highly complex interplay of trans-modifying enzymes, appropriate amino acid activation domains, selective peptide bond-forming domains, and housekeeping thioesterase enzymes is required,” first author Ms Milda Kaniusaite said.

“In this paper we discovered a novel mechanism which explains how the correct peptide sequence is biosynthesised even when the biosynthetic enzymes are faced with many possible substrates to choose from in vivo. Now we know that the peptide bond-forming domain in our assembly lines act as a selectivity filter, and only allow the right amino acid to be incorporated whilst incorrect ones are removed,” she said.

“We also now know how to reprogram peptide assembly lines in terms of peptide bond forming domains, which means if you exchange these domains from one assembly line to another you can incorporate different amino acids. So we are able to synthesise different compounds and potentially create new drugs.”

Ms Kaniusaite, a PhD candidate, said the insights made by the researchers into non-ribosomal peptide biosynthesis were very important to the field.

“There’s a crucial need to understand how these machineries are working in order to design and create new antibiotics,” she said.

“Now that we know how to do this and how to control the process, we can biosythesise a desired peptide sequence into potentially great new antibiotics, which is really exciting.”

GPAs are used to counter infections such as Staphylococcus aureus, Enterococcus spp, and Clostridium difficile.

This article was originally published on the Monash BDI website and was republished here with permission.

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