Research on Antibiotic Resistance in Bacteria
Bacterial infections have become a very serious issue of public health as a result of resistance developed or acquired toward almost all the antibiotics that are in use today. It has become clear that bacteria have the potential to develop resistance fairly easy toward an antibiotic due to the high mutagenesis rate of its genome and the genetic cross-talking among bacteria.
Our focus is to understand the signaling mechanisms involved in induction of antibiotic resistance factors in pathogenic bacteria and especially in methicillin–resistant Staphylococcus aureus. This strain has acquired resistance to almost all the clinically used antibiotics including vancomycin, an antibiotic of the last resort.
The phenomenon of bacterial and viral resistance has raised the questions: Can we inhibit bacterial or viral infections without giving rise to resistance. To put it differently: Is there a resistance-proof biological target? If this is possible, then what biological properties a resistance-proof target should have? Our group is investigating the answers to these questions and the solutions to these problems.
Our group is interested in looking closely at the fusion process of HIV virus with the host cells, and proteins involved in this step. The envelope glycoprotein complex is of special interest. Chemical and biological tools will be used to study the protein-protein interactions involved in the formation of this complex and biophysical methods will be used to quantitatively analyze these interactions.
(Undergraduate, graduate students and postdocs from the Dr. Golemi-Kotra group are underlined in the following publications)
1. Dalal V, Kumar P, Rakhaminov G, Qamar A, Fan X, Hunter H, Tomar S, Golemi-Kotra D* and Kumar P*. Repurposing an Ancient Protein Core Structure: Structural Studies on FmtA, a Novel Esterase of Staphylococcus aureus. J. Mol. Biol. Jun 28. pii: S0022-2836(19)30408-5. doi: 10.1016/j.jmb.2019.06.019. [Epub ahead of print].
2. Tajbakhsh G. and Golemi-Kotra D. The dimerization interface in VraR is essential for induction of the cell wall stress response in Staphylococcus aureus: a potential druggable target. BMC Microbiol. 2019 Jul 5;19(1):153. doi: 10.1186/s12866-019-1529-0.
3. Rahman MM, Hunter HN, Prova S, Verma V, Qamar A, Golemi-Kotra D. The Staphylococcus aureus Methicillin Resistance Factor FmtA Is a D-Amino Esterase That Acts on Teichoic Acids. MBio. 2016 Feb 9;7(1). pii: e02070-15. doi: 10.1128/mBio.02070-15. Highlighted in Faculty 1000 Prime by Yo Luo (University of Saskatchewan).
4. Singh S, Katiki, M. Gill P, Kumar P*, and Golemi-Kotra D*. Active Site Plasticity is Essential for Carbapenem-Hydrolyzing Class D β-Lactamase Catalysis as Revealed by OXA-58 Structural Studies. Antimicrob. Agents Chemother. 2015, 60, 75-86. (*Corresponding authors).
5. Patel, K and Golemi-Kotra, D. Signaling Mechanism by the Staphylococcus aureus Two-Component System LytSR: Role of Acetyl Phosphate in Bypassing the Cell Membrane Electrical Potential Sensor LytS. F1000Research, 2015. Version 2. F1000Res. 4:79. doi: 10.12688/ f1000research.6213.2.
6. Muzamal U, Gomez D, and Golemi-Kotra D. Diversity of two-component systems: insights into the signal transduction mechanism by the Staphylococcus aureus two-component system GraSR. F1000Research 2014, 3:252 (doi: 10.12688/f1000research.5512.1)
7. Shala A, Patel K H, Golemi-Kotra D* and Audette G*. Expression, Purification, Crystallization and Preliminary X-ray Analysis of the Receiver Domain of the Staphylococcus aureus LytR Protein. October 2013. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2013 Dec;69(Pt 12):1418-21. doi: 10.1107/S1744309113030972. [Epub 2013 Nov 29], (*Corresponding authors).
8. Fridman M, Williams GD, Muzamal U, Hunter HN, Siu KW, Golemi-Kotra D. Two unique phosphorylation-driven signaling pathways crosstalk in Staphylococcus aureus to modulate the cell wall charge: Stk1/Stp1 meets GraSR. Biochemistry. 2013, 52,7975-86. [Epub, 2013 Oct 9]. Highlighted in Faculty 1000 Prime by Dr. Suzanne Walker (Harvard Medical School)
9. Leonard P, Golemi-Kotra D and Stock A. Phosphorylation-dependent conformational changes and domain rearrangements in Staphylococcus aureus VraR activation. Proc. Natl. Acad. Sci. USA. 2013. 110(21):8525-30. [Epub 2013 May 6]. Highlighted in Faculty 1000 Prime by Drs. H. Jane Dyson and Rebecca Berlow (The Scripps Research Institute).
10. Rob T, Preet G, Golemi-Kotra D. and Wilson D. An Electrospray MS-coupled Microfluidic Device for Sub-second Hydrogen/Deuterium Exchange Pulse-labelling Reveals Allosteric Effects in Enzyme Inhibition. Lab on a Chip. 2013. 13(13):2528-32.[Epub 2013 Feb 21].
11. Zhao Y, Verma V, Belcheva A, Singh A, Fridman M, and Golemi-Kotra D. Staphylococcus aureus methicillin-resistance factor fmtA is regulated by the global regulator SarA. PLOS One. 2012;7(8): e43998. doi: 10.1371/journal.pone.0043998. [Epub 2012 Aug 30].
12. Qamar A, Golemi-Kotra D. Dual roles of FmtA in Staphylococcus aureus cell wall biosynthesis and autolysis. Antimicrob Agents Chemother. 2012, 56, 3797-805.
13. Belcheva A, Verma V, Korenevsky A, Fridman M, Kumar K, Golemi-Kotra D. Roles of DNA sequence and sigma A factor in transcription of the vraSR operon. J Bacteriol. 2012,194, 61-71 [Epub 2011 Oct 21].
14. Verma, V., Testero, S.A., Amini, A., Wei, W., Liu, J. Balachandran, N., Monoharan, T., Stynes, S., Kotra L.P. and Golemi-Kotra, D. The Hydrolytic Mechanism of OXA-58, a Carbapenem-hydrolyzing Class D β-lactamase from Acinetobacter baumannii. J Biol Chem 2011, 286(43):37292-303 [Epub 2011 Aug 31].