Tuberculosis (TB) is a priority disease for the World Health Organization (WHO), and the emergence of multidrug-resistant Mycobacterium tuberculosis (Mtb) isolates poses an enormous threat to TB intervention efforts. South Africa has a rich history of medicinal plant use for treatment of respiratory ailments and infections, as well as HIV. Amongst the traditional and complementary medicines (T/CAM), Sutherlandia frutescens (SF) is commonly used to alleviate respiratory and HIV-associated conditions/ailments. Recent analysis of an NIH-sponsored clinical trial of the safety of SF consumption by HIV+ individuals suggests that SF may reduce the bactericidal effects of first-line isoniazid (INH) therapy for TB, which could contribute to TB transmission and the emergence of multidrug- resistant (MDR) Mtb bacilli. The revision application submitted here will explore the potential for SF to hinder INH bactericidal efficacy. Specifically, it will investigate the capacity of SF to inhibit intracellular effector molecules, including nitric oxide and reactive oxygen species, and to alter the mycobacterial SOS response. In addition, it will address the potential for SF to block INH killing of Mtb in culture and to block INH killing of Mtb in an aerosol infection humanized mouse model. Outcomes will focus on SF-dependent effects on INH efficacy and comparative organ pathology during treatment. Consistent with the research aims of the parent grant (U01HD085531), the study will apply a combination of mycobacterial reporter mutants and advanced florescence microscopy to investigate the role of SOS- dependent mutagenesis in Mtb exposed to INH and SF as a key molecular mechanism driving the emergence of MDR-TB. In summary, the project aims to address a long-standing question among practicing South African and international infectious disease clinicians and health policy makers around the impact of T/CAMs on the efficacy of frontline anti-TB chemotherapy. To this end, it combines a strong scientific rationale with a collaborative team comprising South African and U.S. researchers with the necessary expertise. As such, the project responds directly to the FOA in ensuring support for relevant scientific research led by SA investigators from underrepresented backgrounds, and conducted at research facilities in South Africa which are proximal to the disease.

Public Health Relevance

This application is in response to Request for Applications: Funding Opportunity Announcement number RFA-AI-16-083 (Revision Applications for U.S.-South Africa Program for Collaborative Biomedical Research). The project addresses key implications of the use of Sutherlandia frutescens (SF) by individuals at risk for tuberculosis (TB) and HIV, which are health priorities in South Africa. It is expected that the evidence generated in this study will inform health policies on the use of SF and other complementary and alternative medicines in relation to MDR-TB development. A central aim of the project is to leverage the strength in natural products research at the University of the Western Cape (UWC) while developing the capacity of UWC for biomedical research, particularly in TB. To this end, the project will establish a partnership between UWC, a historically disadvantaged institution, and the University of Cape Town (UCT), which is one of the leading institutions in biomedical research in South Africa. In addition, two of the South African PI's are defined as Black South Africans according to South African legislation which conforms to the purpose of the call to ?increase the number of underrepresented scientists engaged in research collaboration in support of emerging public health needs in the areas of tuberculosis, HIV/AIDS?.?.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZRG1)
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Russo, Denise
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University of Cape Town
South Africa
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Ditse, Zanele; Lamers, Meindert H; Warner, Digby F (2017) DNA Replication in Mycobacterium tuberculosis. Microbiol Spectr 5:
Warner, Digby F; Rock, Jeremy M; Fortune, Sarah M et al. (2017) DNA Replication Fidelity in the Mycobacterium tuberculosis Complex. Adv Exp Med Biol 1019:247-262
Reiche, Michael A; Warner, Digby F; Mizrahi, Valerie (2017) Targeting DNA Replication and Repair for the Development of Novel Therapeutics against Tuberculosis. Front Mol Biosci 4:75