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Darren Creek     Senior Scientist or Principal Investigator 
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Darren Creek published an article in February 2019.
Research Keywords & Expertise See all
0 A
0 Drug Metabolism
0 Malaria
0 Mass Spectrometry
0 Metabolomics
0 Parasitic diseases
Top co-authors See all
Susan A. Charman

163 shared publications

Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville, Melbourne, Victoria 3052 Australia

Malcolm J. McConville

143 shared publications

Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, The University of Melbourne, Parkville, Australia

Rodolfo Marquez

95 shared publications

Department of Chemistry, University of Glasgow, Glasgow, United Kingdom

Kevin J. Saliba

67 shared publications

Research School of Biology; The Australian National University; 134 Linnaeus Way Acton ACT 2601 Australia

Peter Meikle

63 shared publications

Baker Heart and Diabetes Institute, Melbourne, Australia

79
Publications
40
Reads
4
Downloads
631
Citations
Publication Record
Distribution of Articles published per year 
(2005 - 2019)
Total number of journals
published in
 
33
 
Publications See all
Article 0 Reads 0 Citations 3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) Derivatives with Potent in Vitro and in Vivo Antimalarial Activity Lian Xue, Da-Hua Shi, Jitendra R. Harjani, Fei Huang, Julia ... Published: 04 February 2019
Journal of Medicinal Chemistry, doi: 10.1021/acs.jmedchem.8b01799
DOI See at publisher website
Article 0 Reads 0 Citations Comparative Metabolomics and Transcriptomics Reveal Multiple Pathways Associated with Polymyxin Killing in Pseudomonas a... Mei-Ling Han, Yan Zhu, Darren J. Creek, Yu-Wei Lin, Alina D.... Published: 08 January 2019
mSystems, doi: 10.1128/msystems.00149-18
DOI See at publisher website PubMed View at PubMed ABS Show/hide abstract
Pseudomonas aeruginosa has been highlighted by the recent WHO Global Priority Pathogen List due to multidrug resistance. Without new antibiotics, polymyxins remain a last-line therapeutic option for this difficult-to-treat pathogen. The emergence of polymyxin resistance highlights the growing threat to our already very limited antibiotic armamentarium and the urgency to understand the exact mechanisms of polymyxin activity and resistance. Integration of the correlative metabolomics and transcriptomics results in the present study discovered that polymyxin treatment caused significant perturbations in the biosynthesis of lipids, lipopolysaccharide, and peptidoglycan, central carbon metabolism, and oxidative stress. Importantly, lipid A modifications were surprisingly rapid in response to polymyxin treatment at clinically relevant concentrations. This is the first study to reveal the dynamics of polymyxin-induced cellular responses at the systems level, which highlights that combination therapy should be considered to minimize resistance to the last-line polymyxins. The results also provide much-needed mechanistic information which potentially benefits the discovery of new-generation polymyxins.
Article 1 Read 0 Citations Discovery and Validation of Clinical Biomarkers of Cancer: A Review Combining Metabolomics and Proteomics Anubhav Srivastava, Darren John Creek Published: 26 November 2018
PROTEOMICS, doi: 10.1002/pmic.201700448
DOI See at publisher website
Article 0 Reads 0 Citations Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-R... Mei-Ling Han, Xiaofen Liu, Tony Velkov, Yu-Wei Lin, Yan Zhu,... Published: 16 November 2018
Frontiers in Microbiology, doi: 10.3389/fmicb.2018.02776
DOI See at publisher website PubMed View at PubMed ABS Show/hide abstract
Background: Polymyxins are a last-line class of antibiotics against multidrug-resistant Acinetobacter baumannii; however, polymyxin resistance can emerge with monotherapy. Therefore, synergistic combination therapy is a crucial strategy to reduce polymyxin resistance.
Article 0 Reads 0 Citations Mechanistic Insights From Global Metabolomics Studies into Synergistic Bactericidal Effect of a Polymyxin B Combination ... Maytham Hussein, Mei-Ling Han, Yan Zhu, Elena K. Schneider-F... Published: 10 November 2018
Computational and Structural Biotechnology Journal, doi: 10.1016/j.csbj.2018.11.001
DOI See at publisher website PubMed View at PubMed ABS Show/hide abstract
Polymyxins are amongst the most important antibiotics in modern medicine, in recent times their clinical utility has been overshadowed by nosocomial outbreaks of polymyxin resistant MDR Gram-negative ‘superbugs’. An effective strategy to surmount polymyxin resistance is combination therapy with FDA-approved non-antibiotic drugs. Herein we used untargeted metabolomics to investigate the mechanism(s) of synergy between polymyxin B and the selective estrogen receptor modulator (SERM) tamoxifen against a polymyxin-resistant MDR cystic fibrosis (CF) Pseudomonas aeruginosa FADDI-PA006 isolate (polymyxin B MIC=8 mg/L , it is an MDR polymyxin resistant P. aeruginosa isolated from the lungs of a CF patient). The metabolome of FADDI-PA006 was profiled at 15 min, 1 and 4 h following treatment with polymyxin B (2 mg/L), tamoxifen (8 mg/L) either as monotherapy or in combination. At 15 min, the combination treatment induced a marked decrease in lipids, primarily fatty acid and glycerophospholipid metabolites that are involved in the biosynthesis of bacterial membranes. In line with the polymyxin-resistant status of this strain, at 1 h, both polymyxin B and tamoxifen monotherapies produced little effect on bacterial metabolism. In contrast to the combination which induced extensive reduction (≥ 1.0-log2-fold, p ≤ 0.05; FDR ≤ 0.05) in the levels of essential intermediates involved in cell envelope biosynthesis. Overall, these novel findings demonstrate that the primary mechanisms underlying the synergistic bactericidal effect of the combination against the polymyxin-resistant P. aeruginosa CF isolate FADDI-PA006 involves a disruption of the cell envelope biogenesis and an inhibition of aminoarabinose LPS modifications that confer polymyxin resistance.
Article 0 Reads 2 Citations Alterations of Metabolic and Lipid Profiles in Polymyxin-Resistant Pseudomonas aeruginosa Mei-Ling Han, Yan Zhu, Darren J. Creek, Yu-Wei Lin, Dovile A... Published: 25 May 2018
Antimicrobial Agents and Chemotherapy, doi: 10.1128/aac.02656-17
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Multidrug-resistant Pseudomonas aeruginosa presents a global medical challenge, and polymyxins are a key last-resort therapeutic option. Unfortunately, polymyxin resistance in P. aeruginosa has been increasingly reported. The present study was designed to define metabolic differences between paired polymyxin-susceptible and -resistant P. aeruginosa strains using untargeted metabolomics and lipidomics analyses. The metabolomes of wild-type P. aeruginosa strain K ([PAK] polymyxin B MIC, 1 mg/liter) and its paired pmrB mutant strains, PAKpmrB6 and PAKpmrB12 (polymyxin B MICs of 16 mg/liter and 64 mg/liter, respectively) were characterized using liquid chromatography-mass spectrometry, and metabolic differences were identified through multivariate and univariate statistics. PAKpmrB6 and PAKpmrB12, which displayed lipid A modifications with 4-amino-4-deoxy-l-arabinose, showed significant perturbations in amino acid and carbohydrate metabolism, particularly the intermediate metabolites from 4-amino-4-deoxy-l-arabinose synthesis and the methionine salvage cycle pathways. The genomics result showed a premature termination (Y275stop) in speE (encoding spermidine synthase) in PAKpmrB6, and metabolomics data revealed a decreased intracellular level of spermidine in PAKpmrB6 compared to that in PAKpmrB12. Our results indicate that spermidine may play an important role in high-level polymyxin resistance in P. aeruginosa. Interestingly, both pmrB mutants had decreased levels of phospholipids, fatty acids, and acyl-coenzyme A compared to those in the wild-type PAK. Moreover, the more resistant PAKpmrB12 mutant exhibited much lower levels of phospholipids than the PAKpmrB6 mutant, suggesting that the decreased phospholipid level was associated with polymyxin resistance. In summary, this study provides novel mechanistic information on polymyxin resistance in P. aeruginosa and highlights its impacts on bacterial metabolism.
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