Identifying a new polymyxin for antibiotic drug development

The need

Antimicrobial resistance is a leading threat to global public health. If it continues to rise, it could cause an estimated 300 million deaths by 2050. It could also lead to a loss of US$60–100 trillion in global economic output. New antibiotics are urgently needed, but there are few drugs in the development pipeline.

Polymyxins are ‘last-resort’ antibiotics. They are used against multidrug-resistant Gram-negative bacteria. This includes dangerous human pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Use of the currently available polymyxins has been limited, however, because they cause kidney damage in up to 60 per cent of recipients.

Safer and more effective polymyxins could help in the global fight against antimicrobial resistance.

The solution

Professor Jian Li from the Monash Biomedicine Discovery Institute leads a project to discover new antibiotics. His group has developed new-generation polymyxins and tested their efficacy in mice. As polymyxins can cause kidney damage, detailed kidney histopathology is needed to confirm that they are safe to use. Professor Li has worked with the Phenomics Australia Histopathology and Slide Scanning Service since 2013.

The researchers provide fixed tissue samples to the histopathology team each month. The histopathology team sections the kidney samples to capture the cortex, medulla and papilla. They then stain the sections and analyse them using microscopy. A dedicated specialist with expertise in rodent pathobiology and histology provides analysis.

The histopathology team uploads its report, analyses and digitises images to a secure online portal for the researchers to access. The researchers use this information to identify which drug candidates to evaluate further in pre-clinical studies.

To date, the Phenomics Australia Histopathology and Slide Scanning Service has handled over 4000 samples for Professor Li and his team. The project is ongoing.

The platform

The Phenomics Australia Histopathology and Slide Scanning Service provides necropsy and histopathology services. Team members evaluate tissue from mice at all developmental stages. They identify features in tissue samples and determine whether they are strain-related, age-related, incidental or a true diversion from normal.

The techniques used in this project include:

• Tissue preparation – tissues are sectioned and stained for analysis
• Tissue analysis – stained tissue samples are examined using microscopy
• Tissue grading – tissue samples are scored using a standard matrix, which describes the degree of change from normal tissue.

Partners

Monash Biomedicine Discovery Institute

Patents

PCT/AU2016/050915, filed 29 September 2016

PCT/AU2015/050149, filed 1 April 2015

Publications

Yun B et al (2018) Polymyxin B causes DNA damage in HK-2 cells and mice. Archives of Toxicology 92: 2259 – 2271. doi: 10.1007/s00204-018-2192-1

Azad MAK et al (2018) Methionine ameliorates polymyxin-induced nephrotoxicity by attenuating cellular oxidative stress. Antimicrobial Agents and Chemotherapy 62:e01254-17. doi: 10.1128/AAC.01254-17

Zhu C et al (2017) A traceless reversible polymeric colistin prodrug to combat multidrug-resistant (MDR) gram-negative bacteria. Journal of Controlled Release 259: 83–91. doi: 10.1016/j.jconrel.2017.02.005

Banner image supplied by the Phenomics Australia Histopathology and Slide Scanning Service.