Research

Research

My research focuses on the development of a rationale pipeline to identify novel drug targets in Mycobacterium tuberculosis and the discovery of novel drugs to treat drug resistant forms of the bacteria. Currently, i am involved in several projects that span various research areas such as communicable and non-communicable diseases. Another focus area is biomarker discovery that include the design of RNA-aptamer based technologies to facilitate early diagnosis of Tuberculosis and Ebola virus infections. I am also vested in elucidating the effects of mutations on the structure and function of HIV-1 integrase and understanding the structural impact of Mycobacterium tuberculosis KatG mutations on Isonaizid (INH) resistance.

Research Interest

• 3D structural predictions of proteins, peptides and RNA

• Molecular dynamic simulations of protein-ligand and protein-protein interactions

• Docking studies of small ligands and peptides/proteins to target protein receptors

• Computational software development for structural bioinformatics

• Automated pipeline development in drug discovery and HIV drug resistance analysis

Ongoing projects

• Genetic variation: Simulating the functional effects of single nucleotide polymorphisms on human NAT1 gene and understanding the effects of haplotype variation on the solute carrier transporter gene (SLC22A2) ability to transport diabetes drugs in South African Xhosa populations with type 2 diabetes mellitus.

• Drug discovery: In silico identification and testing of novel small molecules against Mycobacterium tuberculosis and more recently against SARS-COV-2 coronavirus

• Resistance mechanisms: Simulating the functional effects of mutations on HIV-1 integrase drug binding and DNA binding, Structural investigations of KatG mutations associated with Isonaizid resistance

• Candidate gene prioritization: Prioritizing co-segregating variants in South African families with Parkinson's disease

• Biomarker discovery: Development of RNA-aptamers for rapid flow diagnosis of Tuberculosis infection and Ebola virus infection

Publications

van der Merwe L, Cloete R, Revera M, Heradien M, Goosen A, Corfield VA, Brink PA, Moolman-Smook JC. (2008) Genetic variation in angiotensin-converting enzyme 2 gene is associated with extent of left ventricular hypertrophy in hypertrophic cardiomyopathy. Hum Genet. 2008 Aug;124(1):57-61. Epub 2008 Jun 17. PMC2469277

McEvoy C.R.E., Cloete R, Muller B, Schurch A.C, van Helden P.D, Gagneux S, Warren R.M, Gey van Pittius N.C. (2012) Comparative analysis of mycobacterium tuberculosis pe and ppe genes reveals high sequence variation and an apparent absence of selective constraints. PLoS One. 2012;7(4):e30593. Epub 2012 Apr 4. PMC3319526

Cloete R, Oppon E, Murungi E, Schubert W-D, Christoffels A. Resistance related metabolic pathways for drug target identification in Mycobacterium tuberculosis. BMC Bioinformatics. 2016;17:1–10. PMC4745158.

Ruben Cloete, Wisdom A Akurugu, Cedric Werely and Alan Christoffels. Structural and functional effects of nucleotide variation on the human TB drug metabolizing enzyme arylamine N-acetyltransferase 1. J Mol Graph Model. 2017 Aug;75:330-339. doi: 10.1016/j.jmgm.2017.04.026. Epub 2017 Jun 10. PMID:28628859 DOI:10.1016/j.jmgm.2017.04.026

du Plessis, J., Cloete, R., Burchell, L., Sarkar, P., Warren, R.M., Christoffels, A., Wigneshweraraj, S. and Sampson, S.L., 2017. Exploring the potential of T7 bacteriophage protein Gp2 as a novel inhibitor of mycobacterial RNA polymerase. Tuberculosis. PMID: 28802409.

Gurwitz KT, Aron S, Panji S, Maslamoney S, Fernandes PL, Judge DP, Ghouila A, Domelevo Entfellner JB, Guerfali FZ, Saunders C, Alzohairy AM, Salifu SP, Ahmed R, Cloete R, Kayondo J, Ssemwanga D, Mulder N. (2017). Designing a course model for distance-based online bioinformatics training in Africa: The H3ABioNet experience. PloS Comput Biol 13(10): e1005715. https://doi.org/10.1371/journal.pcbi.1005715. PMID: 28981516, PMCID: PMC5628786.

Brado, D., Obasa, A. E., Ikomey, G. M., Cloete, R., Singh, K., Engelbrecht, S., Neogi, U., Jacobs, G. B. (2018). Analyses of HIV-1 integrase sequences prior to South African national HIV-treatment program and available of integrase inhibitors in Cape Town, South Africa. Scientific Reports, 8(1), 4709. PMID: 29549274, PMC5856838.

Cloete R, Kapp E, Joubert J, Christoffels A, Malan S. (2018). Molecular modelling and simulation studies of the Mycobacterium tuberculosis multidrug efflux pump protein Rv1258c. PloS One.

Shahbaaz M, Cloete R, Grobbelaar M, Sampson S, Christoffels A. Structure based identification of novel inhibitors against ATP synthase of Mycobacterium tuberculosis: A combined in silico and in vitro study. International journal of biological macromolecules. 2019;135:582–90.

Allam M, Ismail A, Khumalo ZT, Kwenda S, Van Heusden P, Cloete R, et al. Genome sequencing of a severe acute respiratory syndrome Coronavirus 2 isolate obtained from a South African patient with Coronavirus disease 2019. Microbiology resource announcements. 2020;9(27).

Chitongo R, Obasa AE, Mikasi SG, Jacobs GB, Cloete R. Molecular dynamic simulations to investigate the structural impact of known drug resistance mutations on HIV-1C Integrase-Dolutegravir binding. PloS one. 2020;15(5):e0223464.

Isaacs D, Mikasi SG, Obasa AE, Ikomey GM, Shityakov S, Cloete R, et al. Structural comparison of diverse HIV-1 subtypes using Molecular Modelling and Docking analyses of Integrase inhibitors. Viruses. 2020;12(9):936.

Mikasi SG, Gichana JO, Van der Walt C, Brado D, Obasa AE, Njenda D, Messembe M, Lyonga E, Assoumou O, Cloete R, Ikomey GM, Jacobs GB. HIV-1 integrase diversity and resistance-associated mutations and polymorphisms among integrase strand transfer inhibitor-naive HIV-1 patients from Cameroon. AIDS research and human retroviruses. 2020;36(5):450–5.

Obasa AE, Mikasi SG, Brado D, Cloete R, Singh K, Neogi U, et al. Drug resistance mutations against protease, reverse transcriptase and integrase inhibitors in people living with HIV-1 receiving boosted protease inhibitors in South Africa. Frontiers in microbiology. 2020;11:438.

Mikasi SG, Isaacs D, Chitongo R, Ikomey GM, Jacobs GB, Cloete R. Interaction analysis of statistically enriched mutations identified in Cameroon recombinant subtype CRF02_AG that can influence the development of Dolutegravir drug resistance mutations. BMC Infectious Diseases. 2021;21(1):1–12.

Sebate B, Cuttler K, Cloete R, Britz M, Christoffels A, Williams M, et al. Prioritization of candidate genes for a South African family with Parkinson’s disease using in-silico tools. PloS one. 2021;16(3):e0249324.

Cuttler K, Hassan M, Carr J, Cloete R, Bardien S. Emerging evidence implicating a role for neurexins in neurodegenerative and neuropsychiatric disorders. Open Biol. 2021 Oct;11(10):210091. doi: 10.1098/rsob.210091. Epub 2021 Oct 6. PMID: 34610269; PMCID: PMC8492176.

Martin DR, Sibuyi NR, Dube P, Fadaka AO , Cloete R, Onani M, Madiehe A and Meyer M. Aptamer-Based Diagnostic Systems for the Rapid Screening of TB at the Point-of-Care. Diagnostics (Basel, Switzerland). 2021 Jul;11(8). DOI: 10.3390/diagnostics11081352. PMID: 34441287; PMCID: PMC8391981.

Cloete R, Shahbaaz M, Grobbelaar M, Sampson SL, Christoffels A. In silico repurposing of a Novobiocin derivative for activity against latency associated Mycobacterium tuberculosis drug target nicotinate-nucleotide adenylyl transferase (Rv2421c). PLoS One. 2021 Nov 2;16(11):e0259348. doi: 10.1371/journal.pone.0259348. PMID: 34727137.