Pathogen treatment one step closer
- The pathogen Acinetobacter baumannii is one of three highest priority pathogens identified by World Health Organisation (WHO) for which new antibiotics are urgently needed
- Understanding the enzymes that assemble antibiotics which can kill the pathogen is key to altering their structures to target the pathogen more effectively
- Researcher have made a breakthrough in understanding the functions and structures of key enzymes in the assembly of an antibiotic with activity against the pathogen, which could enable more effective versions to be created
One of the WHO’s three critical priority pathogens, Acinetobacter baumannii, for which new antibiotics are urgently needed is one step closer to being tackled. A team of scientists, led by Monash Warwick Alliance Professor of Sustainable Chemistry and researcher at the Monash Biomedicine Discovery Institute Professor Greg Challis have made a breakthrough in understanding the enzymes that assemble the antibiotic enacyloxin.
Acinetobacter baumannii is a pathogen that causes hospital-acquired infections that are very difficult to treat, because they are resistant to most currently available antibiotics.
Previous research in the area has shown that a molecule called enacyloxin is effective against Acinetobacter baumannii. However, the molecule needs to be engineered to make it suitable for treating infections caused by the pathogen in humans.
The first step to achieving this is to understand the molecular mechanisms used to assemble enacyloxin by the bacterium that makes it. In their paper ‘A dual transacylation mechanism for polyketide synthase chain release in enacyloxin antibiotic biosynthesis’ published in the journal Nature Chemistry, the researchers identifed the enzymes responsible for joining the two components of the antibiotic together.
The key enzyme in this process was found to be promiscuous, suggesting it could be harnessed to produce structurally modified versions of the antibiotic.
“Being able to alter the structure of the antibiotic will be key in future studies to optimise it for treating infections in humans,” Professor Greg Challis, who is also a member of the Department of Chemistry at the University of Warwick, said.
In a second paper, titled ‘Structural basis for chain release from the enacyloxin polyketide synthase’ also published in Nature Chemistry, the researchers report the structure of the enzyme and that of a companion protein which plays a key role in the process.
“We found how specific parts of the enzyme and the companion protein recognise each other. Using a computer algorithm to search all publicly available bacterial genomes, we learned that these recognition elements are commonly found in other enzymes and proteins that make antibiotics and anti-cancer drugs,” co-lead author on the structural study, Professor Józef Lewandowski from the University of Warwick said.
“Understanding how the enzymes and their companion proteins recognise each other provides important clues about the evolution of antibiotic production in bacteria. It also has the potential to be exploited for creation of new types of molecules not seen in nature,” Professor Challis said.
This article is based on a media release published originally by the University of Warwick.
About the Monash Biomedicine Discovery Institute
Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.
About the Monash Warwick Alliance
The Monash Warwick Alliance brings together the combined strengths of Monash University and the University of Warwick to deliver world-class learning, collaborative research solutions and engagement through external partners across multiple global sectors.