Dr Ghader Bashiri

PhD

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Senior Research Fellow

Research | Current

My research investigates the molecular basis of complex biological mechanisms with themes in microbial biochemistry, physiology and pathogenesis. I use a multidisciplinary approach and seek to use the latest state-of-the-art methods in molecular/structural biology, biochemistry, computational biology, microbial infection models, and synthetic chemistry. A major focus of my research is on novel metabolic targets for fighting pathogenic bacteria, to understand their mechanism of action, and to combat the worldwide issues of microbial persistence and resistance. My major research strands are outlined below. 

Coenzyme F420 metabolism. F420 plays an essential role in the metabolism of Archaea and a wide range of bacteria through acting as a hydride transfer agent. Over the last ~12 years, my research has been directed towards understanding F420 biosynthesis, as well as its role in bacterial biochemistry and physiology. As a breakthrough in the field, we have recently proposed a markedly revised pathway for F420 biosynthesis. We currently investigate the role coenzyme F420 plays in M. tuberculosis pathogenesis and persistence. 

 

For more information see:

Bashiri G, Antoney J, Jirgis ENM, Ney B, Sreebhavan S, Palmer B, Middleditch M, Greening C, Baker EN, Scott C and C Jackson (2019) A revised biosynthetic pathway for the cofactor F420 in prokaryotes. Nature Communications, 10:1558.

Bashiri G, Rehan AM, Sreebhavan S, Baker HM, Baker EN and CJ Squire (2016) Elongation of the poly-γ-glutamate tail of F420 requires both domains of the F420:γ-glutamyl ligase (FbiB) of Mycobacterium tuberculosis. Journal of Biological Chemistry, 291:6882-6894.

Oyugi M, Bashiri G, Baker EN and K Johnson-Winters (2016) Investigating the reaction mechanism of F420-dependent glucose-6-phosphate dehydrogenase from Mycobacterium tuberculosis: kinetic analysis of the wild-type and mutant enzymes. Biochemistry, 55:5566-5577. 

 

Check out our collaborators: 

Professor Colin Jackson, Australian National University

Associate Professor Chris Greening, Monash University, Australia 

Associate Professor Kayunta Johnson-Winters, University of Texas at Arlington, USA

 

(Bio)synthesis of natural products. Our research on coenzyme F420 has led to the discovery that this cofactor plays a key role in secondary metabolism of bacteria. We are currently investigating biosynthesis of a wide range of natural products whose biosynthesis we have identified as requiring F420, as well as developing a novel chemoenzymatic platform to produce them in the laboratory. 

 

For more information see:

Steiningerova L, Kamenik Z, Gažák R, Kadlcik S, Bashiri G, Man P, Pavlikova M and J Janata (2020) Different reaction specificities of F420H2-dependent reductases facilitate pyrrolobenzodiazepines and lincomycin to fit their biological targets. Journal of the American Chemical Society, 142:3440-3448 (cover illustration).

Ichikawa H, Bashiri G and WL Kelly (2018) Biosynthesis of the thiopeptins and identification of an F420H2‑dependent dehydropiperidine reductase. Journal of the American Chemical Society, 140:10749-10756. 

Wang P, Bashiri G, Gao X, Sawaya MR and Y Tang (2013) Uncovering the enzymes that catalyze the final steps in oxytetracycline biosynthesis. Journal of the American Chemical Society, 135:7138-7141.

 

Check out our collaborators: 

Associate Professor Wendy Kelly, Georgia Institute of Technology, USA

Professor Meifeng Tao, Shanghai Jiao Tong University,China

Professor Margaret Brimble, University of Auckland

 

Isocitrate lyases in mycobacterial metabolism. Isocitrate lyase (ICL) isoforms 1 and 2 enable M. tuberculosis to preferentially use lipids as its carbon source, a metabolic feature that is crucial for chronic infection. We investigate the unique feature of ICL2 in regulating carbon flux between the tricarboxylic acid (TCA) and glyoxylate cycles at high lipid concentrations. We are pursuing this through structural and mechanistic studies of ICLs, with the ultimate aim of developing inhibitors against both ICL isoforms as potential antitubercular agents. 

 

For more information see:

Bhusal RP, Wanting J, Kwai BXC, Reynisson J, Collins A, Sperry J, Bashiri G and IKH Leung (2019) Acetyl-CoA-mediated activation of Mycobacterium tuberculosis isocitrate lyase 2. Nature Communications, 10:4639. 

Bhusal RP, Bashiri G, Kwai BXC, Sperry J and IKH Leung (2017) Targeting isocitrate lyase for the treatments of latent tuberculosis. Drug Discovery Today, 22:1008-1016.

 

Check out our collaborators: 

Dr Ivanhoe Leung, University of Auckland

Associate Professor Jonathan Sperry, University of Auckland

 

Menaquinone metabolism. Menaquinone is the only electron carrier in the respiratory chain of mycobacteria. We have determined a series of crystal structures, at each step of the catalytic cycle, of the enzyme (MenD) that catalyses the committed step reaction of the menaquinone biosynthesis pathway in M. tuberculosis. We now use MenD as a model system to investigate the fundamentals of internal communication within proteins. In addition, we are actively pursuing a structure-based drug discovery approach to target MenD with the ultimate goal of developing a new generation of anti-TB agents. 

 

For more information see:

Bashiri G, Nigon L, Jirgis ENM, Ho T, Stanborough T, Dawes S, Baker EN, Bulloch EMM and JM Johnston (2020) Allosteric regulation of menaquinone (vitamin K2) biosynthesis in the human pathogen Mycobacterium tuberculosis. Journal of Biological Chemistry, 295:3759-3770 (cover illustration). 

Jirgis ENM, Bashiri G, Bulloch EMM, Johnston JM and EN Baker (2016) Structural views along the Mycobacterium tuberculosis MenD reaction pathway illuminate key aspects of thiamin diphosphate-dependent enzyme mechanisms. Structure, 24:1167-1177 (cover illustration).

 

Check out our collaborators: 

Dr Jodie Johnston, University of Canterbury 

Dr Wanting Jiao, Ferrier Research Institute, Victoria University of Wellington 

Dr Daniel Furkert, University of Auckland 

 

Teaching | Current

BioSci 204: Principles of Microbiology 

BioSci 757: Structural Biology 

Postgraduate supervision

Please have a look on findathesis for available post-graduate projects. Alternatively, send me an email directly!

Distinctions/Honours

Sir Charles Hercus Fellow (Health Research Council of New Zealand) 

Areas of expertise

Molecular and structural biology, biochemistry, microbial metabolism 

Selected publications and creative works (Research Outputs)

As of 29 October 2020 there will be no automatic updating of 'selected publications and creative works' from Research Outputs. Please continue to keep your Research Outputs profile up to date.
  • Bashiri, G., Nigon, L. V., Jirgis, E. N. M., Ho, N. A. T., Stanborough, T., Dawes, S. S., ... Johnston, J. M. (2020). Allosteric regulation of menaquinone (vitamin K2) biosynthesis in the human pathogen Mycobacterium tuberculosis. The Journal of biological chemistry, 295 (12), 3759-3770. 10.1074/jbc.ra119.012158
    Other University of Auckland co-authors: Esther Bulloch, Stephanie Dawes
  • Steiningerova, L., Kamenik, Z., Gazak, R., Kadlcik, S., Bashiri, G., Man, P., ... Janata, J. (2020). Different Reaction Specificities of F420H2-Dependent Reductases Facilitate Pyrrolobenzodiazepines and Lincomycin To Fit Their Biological Targets. Journal of the American Chemical Society, 142 (7), 3440-3448. 10.1021/jacs.9b11234
  • Bhusal, R. P., Jiao, W., Kwai, B. X. C., Reynisson, J., Collins, A. J., Sperry, J., ... Leung, I. K. H. (2019). Acetyl-CoA-mediated activation of Mycobacterium tuberculosis isocitrate lyase 2. Nature communications, 10 (1)10.1038/s41467-019-12614-7
    Other University of Auckland co-authors: Brooke Kwai, Jonathan Sperry, Ivanhoe Leung
  • Bashiri, G., Grove, T. L., Hegde, S. S., Lagautriere, T., Gerfen, G. J., Almo, S. C., ... Baker, E. N. (2019). The active site of the Mycobacterium tuberculosis branched-chain amino acid biosynthesis enzyme dihydroxyacid dehydratase contains a 2Fe-2S cluster. The Journal of biological chemistry, 294 (35), 13158-13170. 10.1074/jbc.ra119.009498
    Other University of Auckland co-authors: Christopher Squire
  • Bashiri, G., Antoney, J., Jirgis, E. N. M., Shah, M. V., Ney, B., Copp, J., ... Middleditch, M. (2019). A revised biosynthetic pathway for the cofactor F420 in prokaryotes. Nature communications, 10 (1)10.1038/s41467-019-09534-x
    Other University of Auckland co-authors: Martin Middleditch
  • Ichikawa, H., Bashiri, G., & Kelly, W. L. (2018). Biosynthesis of the Thiopeptins and Identification of an F420H2-Dependent Dehydropiperidine Reductase. Journal of the American Chemical Society, 140 (34), 10749-10756. 10.1021/jacs.8b04238
  • Jirgis, E. N. M., Bashiri, G., Bulloch, E. M. M., Johnston, J. M., & Baker, E. N. (2016). Structural views along the Mycobacterium tuberculosis MenD reaction pathway illuminate key aspects of thiamin diphosphate-dependent enzyme mechanisms. Structure, 24 (7), 1167-1177. 10.1016/j.str.2016.04.018
    Other University of Auckland co-authors: Esther Bulloch
  • Bashiri, G., Rehan, A. M., Sreebhavan, S., Baker, H. M., Baker, E. N., & Squire, C. J. (2016). Elongation of the poly-γ-glutamate tail of F₄₂₀ requires both domains of the F₄₂₀:γ-glutamyl ligase (FbiB) of Mycobacterium tuberculosis. Journal of Biological Chemistry, 291 (13), 6882-6894. 10.1074/jbc.M115.689026
    Other University of Auckland co-authors: Christopher Squire

Contact details

Primary office location

THOMAS BUILDING - Bldg 110
Level 3, Room 348
3 SYMONDS ST
AUCKLAND CENTRAL
AUCKLAND 1010
New Zealand

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