Investigating the role of siderophore transporters in Mycobacterium tuberculosis as alternative route to combat antibiotic resistance

Daniele Castagnolo (primary)
Institute of Pharmaceutical Science
King's College London
Sanjib Bhakta (secondary)
Biological Sciences
Birkbeck

Abstract

Siderophores are low molecular weight, iron specific chelating agents produced by Mycobacterium tuberculosis with the aim to scavenge iron from the environment and to make the mineral available to the microbial cell. Mycobacteria possess specific protein transporters, such as the MmpL5-MmpS5 system, which export and bring the siderophores in and out the cell.

The aim of the project is to investigate the biology and the mode of action of the siderophore transporters in mycobacteria as well as to exploit them for the development of a Trojan Horse antibiotic-delivery strategy to combat antimicrobial resistance.


References

1. P. Sandhu, Y. Akhter, Siderophore transport by MmpL5-MmpS5 protein complex in Mycobacterium tuberculosis. J. Inorg. Biochem. 2017, 170, 75–84

2. N. Scalacci, A. K. Brown, F. R. Pavan, C. M. Ribeiro, F. Manetti, S. Bhakta, A. Maitra, D. L. Smith, E. Petricci, D. Castagnolo*, Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis. Eur. J. Med. Chem. 2017, 127, 147-158.

3. S. Bhakta, N. Scalacci, A. Maitra, A. K. Brown, S. Dasugari, D. Evangelopoulos, T. D. McHugh, P. N. Mortazavi, A. Twist, E. Petricci, F. Manetti, D. Castagnolo*, Design and synthesis of 1-((1,5-bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N’-((E)-3,7-dimethyl-octa-2,6-dienyl)-ethane-1,2-diamine (SQ109) pyrrole hybrid derivatives: discovery of potent anti-tubercular agents effective against multi-drug resistant mycobacteria. J. Med. Chem. 2016, 59, 2780-2793

4. Phelan, J., Maitra, A., McNerney, R., Nair, M., Gupta, A., Coll, F., … Bhakta, S., & Clark, T. G. The draft genome of Mycobacterium aurum, a potential model organism for investigating drugs against Mycobacterium tuberculosis and Mycobacterium leprae. Int. J. Mycobact., 2015, 4, 207-216 5 Hider, R.C., Kong, X., Chemistry and biology of siderophores. Nat Prod Rep. 2010, 27, 637-57.


BBSRC Area
Molecules, cells and industrial biotechnology
Area of Biology
Cell BiologyChemical BiologyMicrobiology
Techniques & Approaches
BiochemistryBiophysicsChemistryImage ProcessingMicroscopy / ElectrophysiologyMolecular BiologySimulation / Modelling