Screening of South African marine filamentous actinobacteria for antitubercular compounds

Clark, Gesina Maria

Screening of South African marine filamentous actinobacteria for antitubercular compounds

Thesis / Dissertation

2025

Publisher

University of Cape Town

Department

Department of Medicine

Faculty

Faculty of Health Sciences

Abstract

Multidrug-resistant tuberculosis (MDR-TB) is a rampant problem across the globe, perpetuated by the current antimicrobial resistance challenge. To lift the burden, novel antitubercular drugs are needed to treat TB more effectively. The filamentous actinobacteria are a viable source of potential novel antitubercular drugs especially with the advent of technological advancements providing the means to overcome the issues that hampered natural product drug discovery in the past. For example, molecular networking can rapidly dereplicate and verify novel compounds, streamlining the pipeline of drug discovery by allowing antibiotic-producing actinobacteria to be investigated more easily as possible drug sources. Microbial diversity has been linked to the chemical diversity of secondary metabolites and therefore unique actinobacteria have greater potential to produce novel antibiotics. South Africa is one of the most biodiverse countries in the world, however, the antibiotic potential of marine microorganisms has not been fully investigated. This project aimed to screen South African marine filamentous actinobacteria for antitubercular activity and purify the active compound(s) from the most active strains. Nineteen strains which had shown preliminary activity in a previous study were selected for screening, cultured in various liquid media according to their previously demonstrated activity, and extracted. Methanol and ethyl acetate were used to extract the produced secondary metabolites, which were submitted for screening against Mycobacterium tuberculosis (Mtb) in vitro. Streptomyces strain GGUI#16 grown in R2A was identified as a potential novel antibiotic producer as it showed activity against Mtb with an average MIC90 of 5.1 μg/mL, which was lower than the average MIC90 of 5.6 μg/mL seen for isoniazid, a first-line TB drug. GGUI#16 grown in R2A was therefore selected for large scale cultivation and purification by solid phase extraction and high-pressure liquid chromatography. Through a series of bioassay-guided fractionation techniques, the active fractions were successfully isolated and screened against Mtb in vitro. The average MIC90 activity of the crude extract decreased from 5.1 μg/mL to 1.56 μg/mL for the semi-purified compound. Following high resolution mass spectrometry and GNPS analyses, no known compounds were identified in the active fractions – suggesting the active compound(s) may be novel. Future research should aim at increasing the purity of the compound, performing structural elucidation, and conducting preclinical tests to further evaluate the active compound's antitubercular properties.

Keywords

Marine filamentous

South Africa

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