Jahn Nitschke, Robin Huber, Stefania Vossio, Dimitri Moreau, Laurence Marcourt, Katia Gindro, Emerson F. Queiroz, Thierry Soldati, Nabil Hanna
{"title":"Discovery of anti-infective compounds against Mycobacterium marinum after biotransformation of simple natural stilbenes by a fungal secretome","authors":"Jahn Nitschke, Robin Huber, Stefania Vossio, Dimitri Moreau, Laurence Marcourt, Katia Gindro, Emerson F. Queiroz, Thierry Soldati, Nabil Hanna","doi":"10.3389/fmicb.2024.1439814","DOIUrl":null,"url":null,"abstract":"Introduction<jats:italic>Mycobacterium tuberculosis</jats:italic> (Mtb), the causative agent of tuberculosis, remains a serious threat to human health worldwide and the quest for new anti-tubercular drugs is an enduring and demanding journey. Natural products (NPs) have played a significant role in advancing drug therapy of infectious diseases.MethodsThis study evaluated the suitability of a high-throughput infection system composed of the host amoeba <jats:italic>Dictyostelium discoideum</jats:italic> (Dd) and <jats:italic>Mycobacterium marinum</jats:italic> (Mm), a close relative of Mtb, to identify anti-infective compounds. Growth of Dd and intracellular Mm were quantified by using luminescence and fluorescence readouts in phenotypic assays. The system was first benchmarked with a set of therapeutic anti-Mtb antibiotics and then used to screen a library of biotransformed stilbenes.ResultsThe study confirmed both efficacy of established antibiotics such as rifampicin and bedaquiline, with activities below defined anti-mycobacterium susceptibility breakpoints, and the lack of activity of pyrazinamide against Mm. The screening revealed the promising anti-infective activities of <jats:italic>trans</jats:italic>-δ-viniferins and in particular of two compounds 17 and 19 with an IC<jats:sub>50</jats:sub> of 18.1 μM, 9 μM, respectively. Both compounds had no activity on Mm in broth. Subsequent exploration via halogenation and structure-activity relationship studies led to the identification of derivatives with improved selectivity and potency. The modes of action of the anti-infective compounds may involve inhibition of mycobacterial virulence factors or boosting of host defense.DiscussionThe study highlights the potential of biotransformation and NP-inspired derivatization approaches for drug discovery and underscores the utility of the Dd-Mm infection system in identifying novel anti-infective compounds.","PeriodicalId":12466,"journal":{"name":"Frontiers in Microbiology","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Microbiology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.3389/fmicb.2024.1439814","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
IntroductionMycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, remains a serious threat to human health worldwide and the quest for new anti-tubercular drugs is an enduring and demanding journey. Natural products (NPs) have played a significant role in advancing drug therapy of infectious diseases.MethodsThis study evaluated the suitability of a high-throughput infection system composed of the host amoeba Dictyostelium discoideum (Dd) and Mycobacterium marinum (Mm), a close relative of Mtb, to identify anti-infective compounds. Growth of Dd and intracellular Mm were quantified by using luminescence and fluorescence readouts in phenotypic assays. The system was first benchmarked with a set of therapeutic anti-Mtb antibiotics and then used to screen a library of biotransformed stilbenes.ResultsThe study confirmed both efficacy of established antibiotics such as rifampicin and bedaquiline, with activities below defined anti-mycobacterium susceptibility breakpoints, and the lack of activity of pyrazinamide against Mm. The screening revealed the promising anti-infective activities of trans-δ-viniferins and in particular of two compounds 17 and 19 with an IC50 of 18.1 μM, 9 μM, respectively. Both compounds had no activity on Mm in broth. Subsequent exploration via halogenation and structure-activity relationship studies led to the identification of derivatives with improved selectivity and potency. The modes of action of the anti-infective compounds may involve inhibition of mycobacterial virulence factors or boosting of host defense.DiscussionThe study highlights the potential of biotransformation and NP-inspired derivatization approaches for drug discovery and underscores the utility of the Dd-Mm infection system in identifying novel anti-infective compounds.
期刊介绍:
Frontiers in Microbiology is a leading journal in its field, publishing rigorously peer-reviewed research across the entire spectrum of microbiology. Field Chief Editor Martin G. Klotz at Washington State University is supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.