Jian Li Laboratory
Monash Biomedicine Discovery Institute

Jian Li Lab research

Collaborations | Student research projects | Publications

About Professor Jian Li

Professor Jian Li (PhD 2002) is Head of the Antimicrobial Systems Pharmacology Laboratory at the Biomedicine Discovery Institute, Monash University. He is a Web of Science 2015 - 2017 Highly Cited Researcher in Pharmacology & Toxicology. Dr Li has an internationally recognised track record in the pharmacology of polymyxins and the discovery of novel, safer polymyxins. He has 314 publications (including 250 on polymyxins alone) with 14,530 citations and an h-index of 60. Dr Li is an Editor of the International Journal of Antimicrobial Agents and an Associate Editor of BMC Microbiology and Frontiers in Microbiology. He is an invited reviewer for 161 international journals and grant/fellowship applications for 14 international funding bodies. His research is funded by Australian National Health and Medical Research Council (NHMRC), Australian Research Council (ARC), National Institute of Health (NIH) USA, pharmaceutical companies and other grant bodies (52 grants totalling $61.3M since 2004.) He has received numerous awards, including Australian Leadership Award (2013), Australian National Health and Medical Research Council’s Ten of the Best Research Projects (2014) and Australian Academy of Science Jacques Miller Medal (2017).

Our research

Current projects

  1. Optimising clinical use of polymyxins and their synergistic combinations using pharmacokinetics/pharmacodynamics/toxicodynamics (PK/PD/TD) and systems pharmacology
  2. Mechanisms of antibacterial activity, resistance, and toxicity of polymyxins
  3. Development of virtual bacterial cells
  4. Discovery of new-generation polymyxins, novel inhalation formulations, and innovative phage therapy against multidrug-resistant P. aeruginosa, A. baumannii and K. pneumoniae

Visit Professor Jian Li's Monash research profile to see a full listing of current projects.

Research activities

Antibiotics are a cornerstone of modern medicine and over the last century have significantly decreased mortality worldwide. Unfortunately, resistance to these ‘magic bullets’ has become one of the greatest threats to human health that the world faces, now and in the coming decades. If proactive solutions are not found to prevent widespread antibiotic resistance, it is estimated that by 2050 ~10 million people per year will die of infections. The World Health Organization (WHO) has urged all government sectors and society to act on antimicrobial resistance (AMR). In 2017, multidrug-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii were identified by WHO as the highest priority pathogens, which require urgent attention for the discovery of novel antibiotics. Over the last decade, ‘old’ polymyxins are increasingly used as the last defence against these Gram-negative ‘superbugs’ and unfortunately, resistance to polymyxins has been increasingly reported.  As no new antibiotics will be available for Gram-negative ‘superbugs’ in the near future, it is crucial to optimise the clinical use of current antibiotics and develop novel therapies.

My four major research programs are:

1. Optimising clinical use of polymyxins and their synergistic combinations using pharmacokinetics/ pharmacodynamics/toxicodynamics (PK/PD/TD) and systems pharmacology (Funded by NIH and NHMRC)

Recent pharmacological studies, including ours, indicate that plasma concentrations of colistin and polymyxin B are sub-optimal in a large proportion of patients, even with the upper limit of their approved daily doses. Unfortunately, nephrotoxicity is the major dose-limiting adverse effect, and it is not possible to simply increase the daily doses of colistin (as an inactive prodrug colistimethate) or polymyxin B. Our polymyxin pharmacology research over the last two decades has led to the first scientifically-based dosing recommendations for colistin, which has been employed by the European Medicines Agency (EMA) and many hospitals around the world. This project aims to optimise the clinical use of colistin and polymyxin B via intravenous and inhalation administration using PK/PD/TD. Our pharmacological studies demonstrated that highly active polymyxin combination therapy provides a means to increase bacterial killing while minimising resistance and toxicity. We are employing systems pharmacology to identify novel polymyxin combinations and develop innovative dosing strategies.

Figure 1

2. Mechanisms of antibacterial activity, resistance and toxicity of polymyxins (Funded by NIH and NHMRC)

Even though polymyxins became available in the clinic more than 50 years ago, there is still limited information on how they kill bacterial cells, cause resistance, and induce toxicity. Our recent omics and microbiological studies  led to the discovery of novel mechanisms of polymyxin resistance, including loss of LPS in A. baumannii and deacylation in P. aeruginosa. We have demonstrated that polymyxin-induced apoptosis plays a key role in their nephro-, pulmonary and immune-toxicity. Using immunohistochemical, biochemical and transcriptomics, we were the first to report that polymyxins activate multiple apoptosis pathways in renal tubular, neuron, lung epithelial cells, macrophages and neutrophils. We are particularly interested in: (a) identifying the exact mechanism(s) of polymyxin activity and resistance in bacteria, (b) revealing the intracellular trafficking of polymyxins in mammalian cells, and (c) elucidating the interplay of the multiple key apoptosis pathways activated by polymyxins. A multi-disciplinary approach is employed, including cell biology, correlative microscopy, mass spectrometry imaging, genomics, transcriptomics, proteomics, metabolomics and bioinformatics. The mechanistic information obtained is essential for optimising polymyxin use in patients and discovering safer new-generation polymyxins.

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3. Development of virtual bacterial cells using systems pharmacology and computational biology (Funded by NHMRC and NIH)

There are significant gaps in the knowledge base of the exact mechanisms of activity and resistance to antibiotics in P. aeruginosa, A. baumannii and K. pneumoniae. A systems pharmacology approach (including genomics, transcriptomics, proteomics, metabolomics and lipidomics) is required to decipher the complex interplay of multiple cellular pathways in these problematic ‘superbugs’ in response to antibiotics, such as polymyxins.This project is to develop virtual cell models for P. aeruginosa, A. baumannii and K. pneumoniae using systems pharmacology, computational biology, molecular biology, genome-scale metabolic modelling, and bioinformatics; and subsequently employ the virtual cell models to elucidate the complex bacterial cellular responses to antibiotics and their synergistic combinations. Virtual cell models will provide a very powerful systems pharmacology tool to optimise antibiotic combination therapy and holds significant potential for accelerating biomedical discovery.

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4. Development of new-generation polymyxins, novel inhalation formulations and innovative phage therapy (Funded by NIH)

Our polymyxin discovery program employs novel structure-activity relationship (SAR) and structure-nephrotoxicity relationship (SNR) models and is strongly supported by our 20-year polymyxin pharmacological research. We have established an efficient total synthesis platform to produce novel polymyxins for pharmacological evaluations. A funnelling approach is employed with feed-back loops to continuously refine our SAR/SNR models, thereby informing the design of novel lipopeptides with superior antibacterial activity against Gram-negative 'superbugs', while minimising potential for development of resistance and nephrotoxicity.  We are currently involved in an ongoing pre-clinical polymyxin drug development program which is a National Institutes of Health (NIH) funded joint academic-industry collaboration between Monash University and Qpex Biopharma (USA). This program is based on Monash generated IP and aims to produce new polymyxin peptide clinical candidates with improved safety and efficacy over the currently used drugs, polymyxin B and colistin. To date, this collaboration has received >$10M AUD funding from the NIH and has led to the identification of a lead therapeutic candidate with improved safety and efficacy over the currently used polymyxin drugs. In 2019 this lead candidate and associated IP were licenced to Qpex Biopharma for clinical development.

We have also developed novel antibiotic inhalation formulations with enhanced antibacterial activity and safety, through collaborations with Dr Tony Zhou (Purdue University) and Prof Kim Chan (University of Sydney). Considering the significant potential of phage therapy in treating life-threatening antibiotic-resistant infections, we are developing innovative phage therapy against pandrug-resistant P. aeruginosa, A. baumannii and K. pneumoniae.

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Techniques/expertise

  • In vitro microbiological evaluations (minimum inhibitory concentrations, anti-biofilm measurement, time-kill kinetics, antibiotic synergy studies, dynamic pharmacokinetic/pharmacodynamic planktonic and biofilm models; microfluidic models)
  • In vivo models for antimicrobial efficacy (neutropenic mouse lung, blood, thigh, and wound infection models) and toxicity (mouse nephrotoxicity and pulmonary toxicity models)
  • Mouse and rat pharmacokinetics models
  • Discovery of novel antibiotics
  • Antibiotic pharmacokinetic/pharmacodynamic modelling
  • Antimicrobial systems pharmacology (including genomics, transcriptomics, proteomics, metabolomics and bioinformatic analysis)
  • Genome-scale metabolic modelling and virtual cell modelling
  • Membrane lipidomics
  • Molecular dynamic simulations
  • Peptide synthesis and medicinal chemistry
  • Bioanalysis of antimicrobial agents in biological samples using LC/MS
  • Phage discovery, characterisation and pharmacology

Collaborations

We collaborate with many scientists and research organisations around the world. Some of our more significant national and international collaborators are listed below. Click on the map to see the details for each of these collaborators (dive into specific publications and outputs by clicking on the dots).

Optimising the clinical use of the 'old' last-line polymyxins
Professor Keith Kaye, University of Michigan, USA
Professor Alexandre P. Zavascki, Universidade Federal do Rio Grande do Sul, Brazil
Dr Jason Pougue, University of Michigan, USA
Professor David L. Paterson, University of Queensland
Dr Gauri Rao, University of North Carolina at Chapel Hill, USA

Novel polymyxin combinations using systems pharmacology
Associate Professor Tony Velkov, Department of Pharmacology and Therapeutics, University of Melbourne
Associate Professor Jiangning Song, Monash Bioinformatics platform, Monash University
Professor Tony Purcell, Department of Biochemistry and Molecular Biology, Monash University
Dr Darren Creek, MIPS, Monash University
Professor Brian Tsuji, University at Buffalo, USA

Mechanisms of antibacterial activity, resistance and toxicity of polymyxins
Associate Professor Tony Velkov, Department of Pharmacology and Therapeutics, University of Melbourne
Associate Professor John Boyce, Department of Microbiology, Monash University
Dr Jing Fu, Department of Mechanical Engineering, Monash University
Dr Hsin-Hui Shen, Department of Materials Science and Engineering, Monash University
Dr Eliana Marino Moreno, Monash BDI, Monash University
Dr Samuel Forster, Hudson Institute
Dr James Vince, WEHI

Virtual bacterial cells
Professor Falk Schreiber, Department of Computer and Information Science, University of Konstanz
Associate Professor Jiangning Song, Monash Bioinformatics platform, Monash University

Development of new-generation polymyxins, novel inhalation formulations and innovative phage therapy
Associate Professor Tony Velkov, Department of Pharmacology and Therapeutics, University of Melbourne
Professor Philip Thompson, MIPS, Monash University
Dr Mike Dudley, Qpex Biopharma, San Diego, USA
Dr Scott Hecker, Qpex Biopharma, San Diego, USA
Dr Olga Lomovskaya, Qpex Biopharma, San Diego, USA
Dr David Griffith, Qpex Biopharma, San Diego, USA
Dr Tony Zhou, School of Pharmacy, Purdue University
Professor Kim Chan, School of Pharmacy, University of Sydney
Dr Jeremy Barr, Faculty of Science, Monash University

Student research projects

The Jian Li Lab offers a variety of Honours, Masters and PhD projects for students interested in joining our group. There are also a number of short-term research opportunities available. You are encouraged to contact Professor Jian Li regarding potential projects that align with the presented research themes.