Li Lab

Professor Jian Li
NHMRC Senior Research Fellow
Lab Head, Antimicrobial Research Group
Email: Jian.Li@monash.edu
Phone: +61 3 9903 9702

Biosketch

Jian Li is Professor and an NHMRC Senior Research Fellow (Level B) at the Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne. He completed his PhD (2002) at the University of South Australia before moving to Monash University. He was awarded an NHMRC Career Development Award fellowship    in 2006 and was promoted to a full professor within 10 years after he finished his PhD. Jian has an internationally leading track record in the pharmacology of polymyxins (microbiology, chemistry, pharmacokinetics, pharmacodynamics and nephrotoxicity) and discovery and development of novel polymyxins    against Gram-negative 'superbugs'. The majority of modern polymyxin pharmacology data were reported by his group. Jian's research is very well funded by US NIH and Australian NHMRC (>$27M since 2004). The work from his group has resulted in >150 peer-reviewed papers and book chapters, and the graduation    of 9 PhD students. Jian's research targets an urgent global medical challenge, antibiotic resistance and lack of new antibiotics against Gram-negative 'superbugs'.


Project Areas

My group is focused on re-development of 'old' polymyxins as the last-line therapy against Gram-negative 'superbugs'. As no new antibiotics will be available for Gram-negative 'superbugs' for many years to come, it is crucial to optimize the clinical use of 'old' polymyxins using pharmacokinetics/pharmacodynamics/toxicodynamics  (PK/PD/TD), and and development of novel, safer polymyxins. My major research programs are (1) optimising clinical use of polymyxins and their combinations using PK/PD/TD and systems pharmacology; (2) mechanisms of antibacterial activity, resistance, nephrotoxicity and neurotoxicity of polymyxins; and  (3) discovery of novel safer polymyxins against multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumonia. My pharmacological research provides essential mechanistic information for discovery and development of novel, safer polymyxins.

Major Reviews

  1. Li, J., Nation, R.L., Turnidge, J.D., Milne, R.W., Coulthard, K., Rayner, C.R. and Paterson, D.L. Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. The Lancet Infectious Diseases. 2006, 6:589-601.
  2. Zavascki, A.P., Goldani, L.Z., Li, J., Nation, R.L. Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review. Journal of Antimicrobial Chemotherapy. 2007, 60:1206-1215.
  3. Velkov, T., Thompson, P., Nation, R.L. and Li, J. Structure-activity relationships of polymyxin antibiotics. Journal of Medicinal Chemistry. 2010, 53(5):1898-1916.
  4. Nation, R.L., Velkov, T., Li, J. Colistin and polymyxin B: Are they like peas in a pod or chalk and cheese? Clinical Infectious Diseases. 2014. May 1. [Epub ahead of print].
  5. Velkov, T., Bergen, P.J., Lora-Tamayo, J., Landersdorfer, C.B., and Li, J. PK/PD models in antibacterial development. Current Opinion in Microbiology. 2013. 16(5): 573-579.
  6. Velkov, T., Roberts, K.D., Nation, R.L., Thompson, P.E., Li, J. Pharmacology of polymyxins: new insights into an 'old' class of antibiotics. Future Microbiology. 2013. 8(6):711-724.
Optimising clinical use of polymyxin B
Optimising clinical use of polymyxin B

Key Publications

  1. Sandri, A.M., Landersdorfer, C.B., Jacob, J., Boniatti, M.M., Dalarosa, M.G., Falci, D.R., Behle, T.F., Bordinhão, R.C., Wang, J., Forrest, A., Nation, R.L., Li, J.,* Zavascki AP. Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens. Clinical Infectious Diseases. 2013 57(4):524-531. *Corresponding author.
  2. Sandri, A.M., Landersdorfer, C.B., Jacob, J., Boniatti, M.M., Dalarosa, M.G., Falci, D.R., Behle, T.F., Saitovitch, D., Wang, J., Forrest, A., Nation, R.L., Zavascki, A.P., Li, J. Pharmacokinetics of polymyxin B in patients on continuous venovenous hemodialysis. Journal of Antimicrobial Chemotherapy. 2013. 68(3):674-677.
  3. Garonzik, S.M., Li, J.,* Thamlikitkul, V., Paterson, D.L., Shoham, S., Jacob, J., Silveira, F.P., Forrest, A., Nation, R.L. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically-ill patients from a multi-center study provide dosing suggestions for various categories    of patients. Antimicrobial Agents and Chemotherapy. 2011. 55(7):3284-3294. *Joint first author.
  4. Dudhani, R.V., Turnidge, J.D., Nation, R.L. and Li, J. fAUC/MIC is the most predictive pharmacokinetic/pharmacodynamic Index of colistin against Acinetobacter baumannii in murine thigh and lung infection models. Journal of Antimicrobial Chemotherapy. 2010. 65(9):1984-1990.

Novel polymyxin combinations using systems pharmacology (Funded by NIH and NHMRC)

Recent pharmacological studies, including ours, indicate that plasma concentrations of colistin are sub-optimal in a large proportion of patients, even with the upper limit of the approved daily doses of colistin methanesulfonate. Unfortunately, nephrotoxicity is the major dose-limiting adverse effect,  and it is not possible to simply increase the daily doses of colistin methanesulfonate or polymyxin B. Our pharmacological studies demonstrated that highly active polymyxin combination therapy provides a means to increase bacterial killing while minimising resistance and nephrotoxicity. We are employing  systems pharmacology to identify novel polymyxin combinations and develop innovative dosing strategies.

Systems pharmacology of novel polymyxin combinations
Systems pharmacology of novel polymyxin combinations

Key Publications

  1. Lora-Tamayo, J., Murillo, O., Bergen, P., Nation, R.L., Poudyal, A., Luo, X., Yu, H., Ariza, J., Li, J. Activity of Colistin combined with doripenem at clinically relevant concentrations against multidrug-resistant Pseudomonas aeruginosa in an in vitro dynamic biofilm model. Journal of Antimicrobial Chemotherapy. 2014. 69(9): 2434-2442.
  2. Lee, H.J., Bergen, P.J., Bulitta, J.B., Tsuji, B., Forrest, A., Nation, R.L., and Li, J. Colistin and rifampicin combination: synergistic activity against multidrug-resistant Acinetobacter baumannii in an in vitro PK/PD model. Antimicrobial Agents and Chemotherapy. 2013. 57(8):3738-3745.
  3. Bergen, P.J., Tsuji, B.T., Bulitta, J.B., Forrest, A., Jacob, J., Sidjabat, H.E., Paterson, D.L., Nation, R.L. and Li, J. Synergistic killing of multidrug-resistant Pseudomonas aeruginosa at multiple inocula by colistin combined with doripenem in an in vitro PK/PD model. Antimicrobial Agents and Chemotherapy. 2011. 55(12):5685-5695.

Mechanisms of antibacterial activity, resistance, nephrotoxicity and neurotoxicity of polymyxins (Funded by NIH and NHMRC)

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

Key Publications

  1. Velkov, T., Soon, R.L., Chong, P.L., Huang, J.X., Cooper, A.C., Azad, M.A.K., Baker, M.A., Thompson, P.E., Roberts, K.D., Nation, R.L., Clements, A., Strugnell, R.A. and Li, J. Molecular basis for the increased polymyxin susceptibility of Klebsiella pneumoniae strains with under-acylated lipid A. Innate Immunity. 2013. 19(3):265-277.
  2. Soon, R., Nation, R.L., Hartley, P.G., Larson, I. and Li, J. Atomic force microscopy investigation of the morphology and topography of colistin hetero-resistant Acinetobacter baumannii as a function of growth phase, and in response to colistin treatment. Antimicrobial Agents and Chemotherapy. 2009, 53(12):4979-4986.
  3. Moffatt, J.H., Harper, M., Harrison, P., Hale, J.D.F., Vinogradov, E., Seemann, T., Henry, R., Crane, B., Michael, F. St., Cox, A.D., Adler, B., Nation, R.L., Li, J. and Boyce, J.D. Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide. Antimicrobial Agents and Chemotherapy. 2010. 54(12):4971-4977.
  4. Azad, M.A.K., Finnin, B.A., Poudyal, A., Davis, K., Li, J.H., Hill, P.A., Nation, R.L., Velkov, T., Li, J. Polymyxin B induces apoptosis in kidney proximal tubular cells. Antimicrobial Agents and Chemotherapy. 2013. 57(9):4329-4335.
  5. Dai, C., Li, J., Tang, S., Li, J.* and Xiao, X.L. Colistin-induced nephrotoxicity in mice involves the mitochondrial, death receptor, and endoplasmic reticulum pathways. Antimicrobial Agents and Chemotherapy. 2014. 58(7):4075-4085. *Joint corresponding author.

Discovery of safer new-generation polymyxins (Funded by NIH)

Unlike many failed polymyxin discovery projects, our discovery program employs novel structure-activity relationship (SAR) and structure-nephrotoxicity relationship (SNR) models and is strongly supported by our 15-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. Our program responds in a timely manner to the 10 × '20 Initiative: Pursuing a Global Commitment to Develop 10 New Antibacterial Drugs by 2020.

Key Publications

  1. Velkov, T., Roberts, K.D., Nation, R.L., Wang, J., Thompson, P.E., Li, J. Teaching 'old' polymyxins new tricks: New-generation lipopeptides targeting Gram-negative 'superbugs'. ACS Chemical Biology. 2014. 9(5):1172-1177.
  2. Deris, Z., Swarbrick, J.D., Roberts, K., Azad, M., Akter, J., Horne, A., Nation, R.L., Rogers, K., Thompson, P., Velkov, T., Li, J. Probing the penetration of antimicrobial polymyxin lipopeptides into Gram-negative bacteria. Bioconjugate Chemistry. 2014. 25(4):750-760.
  3. Soon, R., Velkov, T., Chiu, F., Thompson, P.E., Roberts, K., Larson, I., Nation, R.L. and Li, J. Design, synthesis and evaluation of a new fluorescent probe for measuring polymyxin-lipopolysaccharide binding interactions. Analytical Biochemistry. 2011. 66(1):126-133.
  4. Velkov, T., Thompson, P., Nation, R.L. and Li, J. Structure-activity relationships of polymyxin antibiotics. Journal of Medicinal Chemistry. 2010, 53(5):1898-1916.

Key collaborators

Optimising the clinical use of the 'old' last-line polymyxins

Prof Roger L. Nation                         MIPS, Monash University

Prof Alexandre P. Zavascki  Universidade Federal do Rio Grande do Sul, Brazil

Prof Keith Kaye                     Wayne State University University Health Center, USA

Prof Alan Forrest                  University at Buffalo, USA

Prof David L. Paterson         University of Queensland

Prof John Turnidge               University of Adelaide

Dr Andrea Lay Hoon Kwa    Singapore General Hospital, Singapore

Dr Jurgen Bulitta                   MIPS, Monash University

Dr Cornelia Landersdorfer  MIPS, Monash University

Novel polymyxin combinations using systems pharmacology

Dr Jiangning Song                 Monash Bioinformatics platform, Monash University

Prof Tony Purcell                  Department of Biochemistry and Molecular Biology, Monash University

Prof Paul Hertzog                 Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research

Dr Tony Velkov                     MIPS, Monash University

Dr Darren Creek                   MIPS, Monash University

A/Prof Brian Tsuji                University at Buffalo, USA

Mechanisms of antibacterial activity, resistance and nephrotoxicity of polymyxins

Dr John Boyce                       Department of Microbiology, Monash University

Prof Ben Adler                      Department of Microbiology, Monash University

Dr Tony Velkov                     MIPS, Monash University

Dr Jing Fu                               Department of Mechanical Engineering, Monash University

A/Prof Prue Hill                    St. Vincent Hospital, Melbourne

Dr Jinhua Li                           Department of Anatomy and Developmental Biology, Monash University

Dr James Vince                      WEHI

Discovery of safer new-generation polymyxins

Dr Tony Velkov                     MIPS, Monash University

A/Prof Philip Thompson      MIPS, Monash University

Dr Mike Dudley                     Rempex Pharmaceuticals, San Diego, USA

Dr Scott Hecker                     Rempex Pharmaceuticals, San Diego, USA

Dr Olga Lomovskaya            Rempex Pharmaceuticals, San Diego, USA

Dr David Griffith                   Rempex Pharmaceuticals, San Diego, USA

Group Members

Group Administrative Officer and Senior Research Assistant: Ms Heidi Yu

Senior Research Scientists: Dr Jiping Wang, Dr Kade Roberts

Postdoctoral research fellows: Dr Matthew Johnson, Dr Tien Thuy Nguyen, Dr Mohammad Azad, Dr Jo-anne Pinson, Dr Yan Zhu, Mr Soon-Ee Cheah

Research Assistants: Ms Van Nguyen, Ms Jesmin Akter, Ms Jie Lu, Mr Ke Chen, Mr Qingyang Hong.

PhD students: Ms Bo Yun, Mr Hafidz Maifiah, Ms Nusaibah Abdulrahim, Mr Thien Tran.

Current Major Funding (selected from 39 in total since 2006)

  1. US National Institute of Health (National Institute for Allergy and Infectious Diseases) 2012 to 2017. US$4.4M. Targeting superbugs: discovery and development of new broad-spectrum lipopeptides. PD/PI.
  2. US National Institute of Health (National Institute for Allergy and Infectious Diseases) 2014 to 2019. US$4.6M. New tricks for 'old' drugs: PK/PD of polymyxin nonantibiotic combinations. PD/PI.
  3. US National Institute of Health (National Institute for Allergy and Infectious Diseases) 2014 to 2019. US$4.5M.  Novel PK/PD strategies for polymyxin combinations against Gram-negative superbugs. Co-PD/PI.
  4. Australian National Health and Medical Research Council. 2014 to 2018. $664,515 NHMRC Senior Research Fellowship B.
  5. Australian National Health and Medical Research Council. 2015 to 2017. $652,180Targeting the Achilles' heel of polymyxins: eliminating the nephrotoxicity. CIA.
  6. Australian National Health and Medical Research Council. 2015 to 2017. $792,778 Revolutionising the diagnosis and monitoring of CF lung disease. CIC.
  7. Australian National Health and Medical Research Council. 2014 to 2016. $496,515 Novel inhalation formulation of colistin and combination therapy against Gram-negative 'superbugs'. CIC.
  8. Australian National Health and Medical Research Council. 2013 to 2015. $563,021 Novel Targeting NDM-producing 'superbugs': optimising novel combinations with 'old' polymyxins using pharmacological, molecular imaging and systems biology approaches. CIA.

Existing videos/news items on my current staff/projects/students/graduates:

http://monash.edu/news/show/monash-university-awarded-9.8-million-to-fight-antibiotic-resistant-superbugs

http://www.monash.edu.au/news/show/major-nih-grant-to-strike-down-superbugs-1

http://www.whitehouse.gov/the-press-office/2014/06/12/fact-sheet-united-states-and-australia-alliance-future