Soon after earning his medical degree, Alexander Pym left his home in London to work in a rural hospital in KwaZulu-Natal. From 1992 to 1994, he was in charge of TB control for the hospital’s district of Nqutu. He also launched the hospital’s first voluntary HIV testing programme.
He was there just as the HIV/TB epidemic was beginning. At the time, only about 2% of the patients were infected with HIV. Today, hospitals in KwaZulu-Natal face HIV infection rates more like 35% to 40%, and TB and HIV are tightly intertwined.
When Dr Pym returned to London in 1994 to continue his medical training, he worked on some of the first clinical trials of triple therapy for HIV. Until then, HIV was treated with a combination of two drugs. This worked to some extent, but it essentially failed to suppress HIV. With triple therapy, for the first time he could see patients actually getting better and remaining well. That showed him that clinical trials could really have a big impact on treatment. Pym went on for a PhD at the Institut Pasteur in Paris where he continued his focus on TB, studying the tuberculosis vaccine BCG and the genetic mutations that make the bacterium that causes TB, Mycobacterium tuberculosis, resistant to antibiotics.
Dr Pym was drawn back to South Africa in 2006 as he felt he wanted to study HIV and TB in an area of the world that was most affected. He worked at the Tuberculosis Research Unit of the South African Medical Research Council in Durban, and observed that the situation was much worse than in the early 90s. He was astonished to find quite how dramatic the TB/HIV epidemic had become. Durban, in particular, has some of the highest rates of TB and HIV infection in the world.
Dr Pym joined K-RITH in November 2011, and is an Associate Professor in the Department of Medical Microbiology at the University of KwaZulu-Natal’s Nelson R. Mandela School of Medicine. His aim is to improve treatment for TB and HIV by testing new drugs and finding better ways of combining existing drugs. People infected with HIV take three drugs for the rest of their lives. TB treatment lasts six months and includes four drugs. When people with both infections are taking seven drugs a day they face difficulties adhering to the drug regimen as well as unhealthy side effects and dangerous drug-drug interactions.
Get in touch with Alex Pym via firstname.lastname@example.org
The Pym Lab’s research focusses 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 an insurmountable obstacle to its effective 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 our 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 results in suboptimal concentrations of antibiotics which creates an environment favourable for the development of drug resistant mutants. Unlike drug susceptible tuberculosis, treatment outcomes for drug resistant tuberculosis are universally poor due to inefficacious second-line therapy. A second theme to the Pym Laboratory 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
RESEARCH LABORATORY TECHNOLOGIST
Vanisha Munsamy was born and raised in Durban. She completed her BSc degree in Microbiology at the University of KwaZulu-Natal Westville in 2007. Thereafter she worked at the SA-MRC TB Unit on clinical trials and validation studies before obtaining an Honours degree in Medical Microbiology in 2010. Vanisha now works under the guidance of Dr Alexander Pym in collaboration with Bill Jacobs and the Einstein University as a Laboratory Technologist. 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
After an initial period of training in the department of Immuno-Mediated Infectious Diseases of Istituto Superiore di Sanità, where Sary El Daker learned the basics of scientific research through HIV-1 study, he started a PhD in Immunology and Applied Biotechnology at the University of Rome Tor Vergata, performing studies on the role of gamma delta T cells and Myeloid Derived Suppressor Cells during M.tb infection. He moved to the laboratory of Gennaro De Libero at the Singapore Immunology Network, where he improved his knowledge in T-cells activation, animal handling, cell cultures and flow cytometry. He was then granted a Marie Curie Fellowship in the Immunology Department of the Pasteur Institute in Antonio Freitas’ lab. Here, he investigated the mechanisms of immunomodulation, studying the role of regulatory T lymphocytes (T-reg), IL-2 and MDSCs in homeostasis. Using K-RITH’s BSL-3 flow cytometry platforms, Sary is now investigating the antibiotic survival mechanism of M. Tuberculosis in vitro and during infection.
Prudy Manoko Mashika Seepe received her Master’s degree in Medical Biochemistry at the Centre of excellence for TB research, University of Stellenbosch. She was a nominee for the L’Oreal-UNESCO Women in Science Sub-Saharan African Scholarship and was awarded a South African Department of Science and Technology Women in Science fellowship. Prudy’s PhD research entails profiling and characterisation of bioactive secondary metabolites produced by uncultured South African soil micro-organisms.
Patience Shumba completed her Bachelor of Science degree in Biochemistry and Microbiology at the University of KwaZulu-Natal Pietermaritzburg campus (UKZN) in 2013. Her interest in studying diseases which affect humans led to her honours project which aimed at optimising the recombinant expression of Plasmodium falciparum histidine rich protein II for use in malaria diagnosis. She completed her BSc Honours in Biochemistry at UKZN in 2014. Patience is currently enrolled for a Masters degree under the supervision of Dr Alexander Pym. The aim of the 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.
Lynne de Welzen
Lynne de Welzen was born and raised in Westville, Durban. She obtained a BSc in Cellular biology and Microbiology cum laude in 2011 at the University of KwaZulu-Natal, and then went on to complete her Bachelor of Medical Science (Honours) Degree in Medical Microbiology summa cum laude in 2012 at the Nelson R Mandela School of Medicine. Her honours project looked at the Mycobacterium tuberculosis pili gene in various drug resistant clinical isolates. It was this brief introduction to TB that made her determined to learn more about M. tuberculosis and drug resistance. Lynne is currently 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. Her research involves RNA extraction and library preparation of samples for RNA-sequencing on platforms such as the Illumina, RNA Fluorescent in situ hybridization (FISH) and cloning.
RESEARCH LABORATORY TECHNICIAN
Kayleen Brien has Honours and Masters degrees in Biochemistry from the University of KwaZulu-Natal. Her keen interest in TB and HIV research led her to K-RITH. As a K-RITH Laboratory Technician, Kayleen’s main duties 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.
RESEARCH LABORATORY TECHNOLOGIST
Born and raised in Durban, Kashmeel Maharaj grew up with a love for science. In 2007, he achieved a Bachelor of Science: Bio-Medical Sciences degree from the University of KwaZulu-Natal in 2007 and Bachelor of Medical Sciences (Honours) in Human Physiology in 2008. In 2011 he qualified as HPCSA Medical Technician in Microbiology whilst working as Microbiology technician at Lancet’s Tuberculosis diagnostic lab. This sparked his interest in M. tuberculosis research, in particular TB drug resistance. He lives by the motto “What man is a man who does not make the world better?” from the movie Kingdom of Heaven. Kashmeel’s research focuses on diagnosing and characterizing Pyrazinamide resistance in M. tuberculosis, and understanding the phenomena of persistence in M. tuberculosis using molecular biology techniques.
Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance. Nat Genet, advance online publication. doi:10.1038/ng.3548
Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. European Respiratory Journal, 47(2), 564-574. doi:10.1183/13993003.00724-2015
The effect of SLCO1B1 polymorphisms on the pharmacokinetics of rifabutin in African HIV-infected patients with tuberculosis. Antimicrob Agents Chemother. 2015 Oct 19. pii: AAC.01195-15. [Epub ahead of print]
Impact of tuberculosis treatment and antiretroviral therapy on serial RD-1-specific quantitative T-cell readouts (QuantiFERON-TB Gold In-Tube), and relationship to treatment-related outcomes and bacterial burden.
Effective anti-tuberculosis therapy correlates with plasma small RNA. Eur Respir J. 2015 Jun;45(6):1741-4. doi: 10.1183/09031936.00221214. Epub 2015 Mar 5.
Multidrug-resistant tuberculosis and culture conversion with bedaquiline. TMC207-C208 Study Group. N Engl J Med. 2014 Aug 21;371(8):723-32. doi: 10.1056/NEJMoa1313865.