Dr Alexander Pym initially trained as a physician, and was involved in some of the first clinical trials of combination antiretroviral therapy. He completed his PhD at the Institut Pasteur in Paris, where he identified the Type VII secretion system responsible for the export of ESAT6 and its role in the attenuation of the tuberculosis (TB) vaccine BCG. After postdoctoral studies at Stanford studying the fitness and transmission of drug-resistant M. tuberculosis he moved to the South African Medical Research Council where he established a multidrug-resistant TB (MDR-TB) clinical trial site and conducted the first ever formal clinical trials for MDR-TB. This led to the registration of bedaquiline, the first new TB drug in 40 years. Alex moved to the KwaZulu-Natal Research Institute for TB-HIV (K-RITH) in 2011 and established a laboratory focussing on mechanisms of antibiotic resistance and tolerance in M. tuberculosis. Alex is a member of AHRI Faculty, and heads up a laboratory at the Institute. He is an Honorary Clinical Professor at University College London and an Honorary Associate Professor at University of KwaZulu-Natal.
Click here for a full list of publications.
Dr Alex Pym’s research group is focussed on understanding how the TB bacterium is able to tolerate or resist antibiotics. Antibiotic tolerance is poorly understood. The current treatment length for drug susceptible tuberculosis is six months. Administered in clinical trial settings it delivers a cure rate approaching 95%. However, the duration of this treatment has proved a huge obstacle to its successful implementation. To achieve an ultra-short course of treatment new drugs are needed that more effectively eradicate the tiny subpopulations of bacteria that survive the first few weeks of the current treatment.
Two mechanisms could allow drug susceptible organisms to persist in these conditions. Recent evidence has confirmed that for some TB drugs, penetration into pathological lung tissue may result in suboptimal tissue concentrations that impede bacteria killing. Alternatively, a small proportion of organisms are phenotypically antibiotic tolerant, and can survive even in the presence of active drugs. The aim of the Pym Group’s research is to use in vitro and animal models as well as novel human studies to understand the basis of this phenotype and use strategies to overcome it.
Another consequence of lengthy drug treatment duration is poor adherence to therapy. This creates an environment favourable for the development of drug resistant mutants. Unlike drug susceptible TB, treatment outcomes for drug resistant tuberculosis are poor. A second theme to the Pym Group’s research is to use a combination of comparative genomics, functional genetics and animal models to comprehensively understand the mechanisms of drug resistant tuberculosis and translate these findings into better diagnostics and chemotherapy.
Meet the Team
Vanisha Munsamy holds a Master’s degree from UKZN. She previously worked at the SA-MRC TB Unit on clinical trials and validation studies. Vanisha now works under the guidance of Dr Alexander Pym in collaboration with Bill Jacobs and the Einstein University. This collaboration involves work with a fluorophage for detection of Mycobacterium tuberculosis and drug susceptibility testing directly from sputum samples.
Sary El Daker
Postdoctoral Research Fellow
Sary El Daker holds a PhD in Immunology and Applied Biotechnology from the University of Rome Tor Vergata. He was a Marie Curie fellow in the Immunology Department of the Pasteur Institute in Antonio Freitas’ lab, where he investigated the mechanisms of immunomodulation, studying the role of regulatory T lymphocytes (T-reg), IL-2 and MDSCs in homeostasis. Using AHRI’s BSL-3 flow cytometry platforms, Sary is now investigating the antibiotic survival mechanism of M. Tuberculosis in vitro and during infection.
Lynne de Welzen
Lynne de Welzen is investigating transcriptional profiles of various clinical isolates, including susceptible MDR and XDR strains of M. tuberculosis, using RNA-Seq. Her research aims to understand and identify novel mechanisms of drug resistance in M. tb at the transcriptional level by identifying transcriptional changes that lead to drug resistance, or compensate for loss of fitness due to a drug resistance conferring mutation.
Collaborating PhD student
Camus Nimmo is a registrar in respiratory medicine from the UK. He has taken time out of training to study for a PhD at University College London and AHRI. He is investigating the role of minority genetic populations of Mycobacterium tuberculosis, found in sputum and lung tissue samples on the development of drug resistance, using next generation whole genome sequencing.
Patience Shumba holds an Honours degree in Biochemistry from UKZN. The aim of her Master’s project is to use fluorescence activated cell sorting (FACS) to isolate antibiotic survivors in Mycobacterium tuberculosis. The antibiotic survivors can then be characterised using transcriptomics.
Darren graduated with his BSc (Hons) in 2014 from the University of KwaZulu-Natal. He started his Master’s in 2015, working on a project that aimed to characterise drug tolerant Mycobacterium tuberculosis (Mtb) based on their intracellular lipid content using both flow cytometry and microscopy techniques. Darren is also a second-year medical student whilst working part-time on his Master’s project.
Kayleen Brien has Honours and Master’s degrees in Biochemistry from the University of KwaZulu-Natal. Kayleen’s main duties at AHRI include the maintenance and upkeep of BSL2 and BSL3 laboratories. She is also responsible for the processing of clinical sputum samples for downstream applications and laboratory experiments involving drug susceptibility and tolerance assays in mycobacteria.
Selected Recent Publications
Desjardins, C. A., Cohen, K. A., Munsamy, V., Abeel, T., Maharaj, K., Walker, B. J., Shea, T. P., Almeida, D. V., Manson, A. L., Salazar, A., Padayatchi, N., O'Donnell, M. R., Mlisana, K. P., Wortman, J., Birren, B. W., Grosset, J., Earl, A. M., & Pym, A. S. (2016). Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance. Nat Genet, 48(5), 544-551. doi: 10.1038/ng.3548.
Hennig S, Naiker S, Reddy T, Egan D, Kellerman T, Wiesner L, Owen A, McIlleron H, Pym A. (2015). Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis. Antimicrob Agents Chemother. Oct 19;60(1):617-20. doi: 10.1128/AAC.01195-15.
Cohen, K. A., Abeel, T., McGuire, A. M., Desjardins, C. A., Munsamy, V., Shea, T. P., Walker, B. J., Bantubani, N., Almeida, D. V., Alvarado, L... Pym, A. S. & Earl, A. M. (2015). Evolution of extensively drug-resistant tuberculosis over four decades: whole genome sequencing and dating analysis of Mycobacterium tuberculosis isolates from KwaZulu-Natal. PLoS Med, 12(9), e1001880.
Cohen KA, Bishai WR, Pym AS. (2014). Molecular Basis of Drug Resistance in Mycobacterium tuberculosis. Microbiol Spectr. Jun;2(3). doi: 10.1128/microbiolspec.MGM2-0036-2013.
Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, Leimane V, Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, De Paepe E, van Heeswijk RP, Dannemann B; TMC207-C208 Study Group. (2014). Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. Aug 21;371(8):723-32. doi: 10.1056/NEJMoa1313865.