Browsing by Author "Vermeulen, Ross"

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    Characterization of atypical class I lanthipeptides from the marine bacterium thalassomonas viridans XOM25ᵀ
    (Stellenbosch : Stellenbosch University, 2024-03) Vermeulen, Ross; Dicks, Leon Milner Theodore ; Van Staden, Anton du Preez; Trindade, Marla; Stellenbosch University. Faculty of Science. Dept. of Microbiology.
    ENGLISH ABSTRACT: The natural products (NPs) that are produced by living organisms have historically served as a pivotal starting point for numerous highly effective therapeutic agents. These compounds often possess distinct chemical structures that enable valuable mechanisms and modes of biological activity. Natural products are thus a promising reservoir that potentially contains the key to the treatment of diseases like cancer, infections, resistance, neurological disorders, and even a range of agricultural and environmental challenges. The rate of novel drug discovery is exhibiting a gradual decline. However, recent advancements in biotechnology, such as next-generation sequencing (NGS) and heterologous gene expression, are empowering researchers to access unexplored realms of biological and chemical diversity. Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a class of NPs that have experienced significant growth by combining NGS and heterologous expression. Within the RiPP group, lanthipeptides are characterized by the post-translational installation of lanthionine rings or thioether cross-linkages. The incorporation of lanthionine rings offers several advantages such as enhanced stability and expanded structural diversity at low genetic cost. However, the process of post-translational modification poses distinct challenges when attempting to heterologously produce lanthipeptides exhibiting previously unobserved and markedly distinct characteristics. To date, the majority of described lanthipeptides play an antimicrobial role which provides a competitive advantage to the native producer by inhibiting the growth of similar or closely related species. Recently, a significant number of cryptic lanthipeptides have been heterologously produced which do not exhibit antimicrobial activity against species related to the native host. Many of these seemingly inactive and atypical lanthipeptides originate from Gram-negative bacteria associated with the marine environment. In this work, a significantly dissimilar lanthipeptide operon was identified in the genome of the marine Gram-negative marine bacteria Thalassomonas viridans XOM25T. The operon was used to construct an Escherichia coli BL21 expression system capable of co-producing the peptide substrates and post-translational modification machinery. The target peptides were subsequently isolated, confirmed to contain post-translationally installed lanthionine rings, and designated as the viridisin operon. Finally, the antimicrobial, stereochemical and pharmaceutical potential of the viridisins were assessed. The viridisins have similar stereochemistries to other lanthipeptides from Gram- negative bacteria, and likewise, they do not have antimicrobial properties. However, this study proved that the viridisin were able to modulate zebrafish larvae behavior. While the results of the zebrafish behavioral screening do not provide definitive proof of the mechanisms at play, such findings allude to the remarkable diversity of biological roles that RiPPs fulfil – intended or otherwise.