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Darren Creek     Senior Scientist or Principal Investigator 
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Darren Creek published an article in January 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
Jonathan B. Baell

63 shared publications

Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia

Kevin J. Saliba

60 shared publications

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

Rodolfo Marquez

57 shared publications

Xi'an Jiaotong-Liverpool University

Alexander G. Maier

46 shared publications

Australian National University

Erick Strauss

42 shared publications

Department of Biochemistry, Stellenbosch University, Matieland, 7602, South Africa

52
Publications
14
Reads
4
Downloads
689
Citations
Publication Record
Distribution of Articles published per year 
(2005 - 2019)
Total number of journals
published in
 
29
 
Publications See all
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 ABS Show/hide abstract
Polymyxins are a last-line therapy against multidrug-resistant Pseudomonas aeruginosa; however, resistance to polymyxins has been increasingly reported. Therefore, understanding the mechanisms of polymyxin activity and resistance is crucial for preserving their clinical usefulness. This study employed comparative metabolomics and transcriptomics to investigate the responses of polymyxin-susceptible P. aeruginosa PAK (polymyxin B MIC, 1 mg/liter) and its polymyxin-resistant pmrB mutant PAKpmrB6 (MIC, 16 mg/liter) to polymyxin B (4, 8, and 128 mg/liter) at 1, 4, and 24 h, respectively. Our results revealed that polymyxin B at 4 mg/liter induced different metabolic and transcriptomic responses between polymyxin-susceptible and -resistant P. aeruginosa. In strain PAK, polymyxin B significantly activated PmrAB and the mediated arn operon, leading to increased 4-amino-4-deoxy-L-arabinose (L-Ara4N) synthesis and the addition to lipid A. In contrast, polymyxin B did not increase lipid A modification in strain PAKpmrB6. Moreover, the syntheses of lipopolysaccharide and peptidoglycan were significantly decreased in strain PAK but increased in strain PAKpmrB6 due to polymyxin B treatment. In addition, 4 mg/liter polymyxin B significantly perturbed phospholipid and fatty acid levels and induced oxidative stress in strain PAK, but not in PAKpmrB6. Notably, the increased trehalose-6-phosphate levels indicate that polymyxin B potentially caused osmotic imbalance in both strains. Furthermore, 8 and 128 mg/liter polymyxin B significantly elevated lipoamino acid levels and decreased phospholipid levels but without dramatic changes in lipid A modification in wild-type and mutant strains, respectively. Overall, this systems study is the first to elucidate the complex and dynamic interactions of multiple cellular pathways associated with the polymyxin mode of action against P. aeruginosa. IMPORTANCE 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....
Article 0 Reads 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
CONFERENCE-ARTICLE 14 Reads 0 Citations Metabolomics helps to unravel the mode of action of novel anti-malarial compounds Anubhav Srivastava, Matthew Todd, Darren Creek Published: 20 November 2017
The 2nd International Electronic Conference on Metabolomics, doi: 10.3390/iecm-2-04990
DOI See at publisher website ABS Show/hide abstract

Access to large phenotypic screens has enabled the discovery of a number of compounds which can kill the malaria parasite in vitro. Translating these findings into new anti-malarial drugs faces a number of challenges. Finding the mode of action of these compounds can help in focussing efforts to develop the most promising compounds and help in designing new combination therapies targeting different pathways in the parasite to overcome drug-resistance. Using a microplate-based, untargeted metabolomics analysis of Plasmodium falciparum, we investigated the mode of action of 11 potent antimalarial compounds obtained from the Medicines for Malaria Venture and the Open Source Malaria project. This approach revealed significant metabolic perturbation associated with the most potent compounds, and identified the most likely pathways targeted by each compound. The major metabolic pathway intermediates which were found to be perturbed were from the pyrimidine biosynthesis pathway, glycolysis, phospholipid metabolism and haemoglobin degradation. Multivariate analyses allowed classification of some novel compounds that targeted the same biochemical pathways as two known anti-malarials, Atovaquone and Cipargamin. Interestingly, compounds showing similar biochemical activities did not always have similar chemical structures.  This study shows that a simple and efficient metabolomics assay can rapidly reveal the biochemical basis of the mode of action of newly discovered anti-malarials. This information can be used for prioritising compounds before progressing them through the optimization pipeline and further development. 

PREPRINT-CONTENT 0 Reads 1 Citation Mutations in the pantothenate kinase ofPlasmodium falciparumconfer diverse sensitivity profiles to antiplasmodial pantot... Erick T. Tjhin, Christina Spry, Alan L. Sewell, Annabelle Ho... Published: 16 May 2017
Pharmacology and Toxicology, doi: 10.1101/137182
DOI See at publisher website ABS Show/hide abstract
The malaria-causing blood stage ofPlasmodium falciparumrequires extracellular pantothenate for proliferation. The parasite converts pantothenate into coenzyme A (CoA) via five enzymes, the first being a pantothenate kinase (PfPanK). Multiple antiplasmodial pantothenate analogues, including pantothenol and CJ-15,801, kill the parasite by targeting CoA biosynthesis/utilisation. Their mechanism of action, however, remains unknown. Here, we show that parasites pressured with pantothenol or CJ-15,801 become resistant to these analogues. Whole-genome sequencing revealed mutations in one of two putative PanK genes (Pfpank1) in each resistant line. These mutations significantly alterPfPanK activity, with two conferring a fitness cost, consistent withPfpank1coding for a functional PanK that is essential for normal growth. The mutants exhibit a different sensitivity profile to recently-described, potent, antiplasmodial pantothenate analogues, with one line being hypersensitive. We provide evidence consistent with different pantothenate analogue classes having different mechanisms of action: some inhibit CoA biosynthesis while others inhibit CoA-utilising enzymes.
Article 0 Reads 3 Citations Metabolomics-Based Elucidation of Active Metabolic Pathways in Erythrocytes and HSC-Derived Reticulocytes Anubhav Srivastava, Krystal J. Evans, Anna E. Sexton, Louis ... Published: 01 March 2017
Journal of Proteome Research, doi: 10.1021/acs.jproteome.6b00902
DOI See at publisher website PubMed View at PubMed
Article 0 Reads 12 Citations Stage-Specific Changes in Plasmodium Metabolism Required for Differentiation and Adaptation to Different Host and Vector... Anubhav Srivastava, Nisha Philip, Katie R. Hughes, Konstanti... Published: 27 December 2016
PLOS Pathogens, doi: 10.1371/journal.ppat.1006094
DOI See at publisher website PubMed View at PubMed ABS Show/hide abstract
Malaria parasites (Plasmodium spp.) encounter markedly different (nutritional) environments during their complex life cycles in the mosquito and human hosts. Adaptation to these different host niches is associated with a dramatic rewiring of metabolism, from a highly glycolytic metabolism in the asexual blood stages to increased dependence on tricarboxylic acid (TCA) metabolism in mosquito stages. Here we have used stable isotope labelling, targeted metabolomics and reverse genetics to map stage-specific changes in Plasmodium berghei carbon metabolism and determine the functional significance of these changes on parasite survival in the blood and mosquito stages. We show that glutamine serves as the predominant input into TCA metabolism in both asexual and sexual blood stages and is important for complete male gametogenesis. Glutamine catabolism, as well as key reactions in intermediary metabolism and CoA synthesis are also essential for ookinete to oocyst transition in the mosquito. These data extend our knowledge of Plasmodium metabolism and point towards possible targets for transmission-blocking intervention strategies. Furthermore, they highlight significant metabolic differences between Plasmodium species which are not easily anticipated based on genomics or transcriptomics studies and underline the importance of integration of metabolomics data with other platforms in order to better inform drug discovery and design. Malaria kills almost half a million people worldwide every year and more than two hundred million people are diagnosed with this deadly disease annually. It is caused by the protozoan parasite Plasmodium spp., mostly in sub-Saharan Africa and Asia and is transmitted by bites of infected female Anopheles mosquitoes. Due to an increase in resistance to existing drugs and lack of an effective vaccine, new intervention strategies which target development of parasite in human host and transmission through the mosquito vector are urgently needed. In this study, we explored the metabolic capacity of different developmental stages of the malaria parasite to determine carbon source utilization in different host niches and whether any stage-specific switches in metabolism could be exploited in new therapies aimed at eradicating malaria. Using stable isotope labelling and metabolomics, we have identified considerable nutritional adaptability of malaria parasites between the mammalian host and the mosquito vector. Gene disruption in the rodent malaria parasite P. berghei was used to identify the metabolic pathways which are crucial to the survival and development of the parasite. Our data also point at key metabolic differences in different Plasmodium species highlighting the importance of integrating metabolomics analyses with molecular tools and identifies possible transmission blocking candidates for malaria intervention.
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