Exploitation of Mangrove Endophytic Fungi for Infectious Disease Drug Discovery

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Abstract

There is an acute need for new and effective agents to treat infectious diseases. We conducted a screening program to assess the potential of mangrove-derived endophytic fungi as a source of new antibiotics. Fungi cultured in the presence and absence of small molecule epigenetic modulators were screened against Mycobacterium tuberculosis and the ESKAPE panel of bacterial pathogens, as well as two eukaryotic infective agents, Leishmania donovani and Naegleria fowleri. By comparison of bioactivity data among treatments and targets, trends became evident, such as the result that more than 60% of active extracts were revealed to be selective to a single target. Validating the technique of using small molecules to dysregulate secondary metabolite production pathways, nearly half (44%) of those fungi producing active extracts only did so following histone deacetylase inhibitory (HDACi) or DNA methyltransferase inhibitory (DNMTi) treatment.

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Regulation of fungal secondary metabolism.

Axel A. Brakhage (2013)

Fungi produce a multitude of low-molecular-mass compounds known as secondary metabolites, which have roles in a range of cellular processes such as transcription, development and intercellular communication. In addition, many of these compounds now have important applications, for instance, as antibiotics or immunosuppressants. Genome mining efforts indicate that the capability of fungi to produce secondary metabolites has been substantially underestimated because many of the fungal secondary metabolite biosynthesis gene clusters are silent under standard cultivation conditions. In this Review, I describe our current understanding of the regulatory elements that modulate the transcription of genes involved in secondary metabolism. I also discuss how an improved knowledge of these regulatory elements will ultimately lead to a better understanding of the physiological and ecological functions of these important compounds and will pave the way for a novel avenue to drug discovery through targeted activation of silent gene clusters.

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Big effects from small changes: possible ways to explore nature's chemical diversity.

Helge Bode, Barbara Bethe, Regina Höfs … (2002)

Fungi or bacteria that produce secondary metabolites often have the potential to bring up various compounds from a single strain. The molecular basis for this well-known observation was confirmed in the last few years by several sequencing projects of different microorganisms. Besides well-known examples about induction of a selected biosynthesis (for example, by high- or low-phosphate cultivation media), no overview about the potential in this field for finding natural products was given. We have investigated the systematic alteration of easily accessible cultivation parameters (for example, media composition, aeration, culture vessel, addition of enzyme inhibitors) in order to increase the number of secondary metabolites available from one microbial source. We termed this way of revealing nature's chemical diversity the 'OSMAC (One Strain-Many Compounds) approach' and by using it we were able to isolate up to 20 different metabolites in yields up to 2.6 g L(-1) from a single organism. These compounds cover nearly all major natural product families, and in some cases the high production titer opens new possibilities for semisynthetic methods to enhance even more the chemical diversity of selected compounds. The OSMAC approach offers a good alternative to industrial high-throughput screening that focuses on the active principle in a distinct bioassay. In consequence, the detection of additional compounds that might be of interest as lead structures in further bioassays is impossible and clearly demonstrates the deficiency of the industrial procedure. Furthermore, our approach seems to be a useful tool to detect those metabolites that are postulated to be the final products of an amazing number of typical secondary metabolite gene clusters identified in several microorganisms. If one assumes a (more or less) defined reservoir of genetic possibilities for several biosynthetic pathways in one strain that is used for a highly flexible production of secondary metabolites depending on the environment, the OSMAC approach might give more insight into the role of secondary metabolism in the microbial community or during the evolution of life itself.

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A Historical Overview of the Classification, Evolution, and Dispersion of Leishmania Parasites and Sandflies

Mohammad Akhoundi, Katrin Kuhls, Arnaud Cannet … (2016)

Background The aim of this study is to describe the major evolutionary historical events among Leishmania, sandflies, and the associated animal reservoirs in detail, in accordance with the geographical evolution of the Earth, which has not been previously discussed on a large scale. Methodology and Principal Findings Leishmania and sandfly classification has always been a controversial matter, and the increasing number of species currently described further complicates this issue. Despite several hypotheses on the origin, evolution, and distribution of Leishmania and sandflies in the Old and New World, no consistent agreement exists regarding dissemination of the actors that play roles in leishmaniasis. For this purpose, we present here three centuries of research on sandflies and Leishmania descriptions, as well as a complete description of Leishmania and sandfly fossils and the emergence date of each Leishmania and sandfly group during different geographical periods, from 550 million years ago until now. We discuss critically the different approaches that were used for Leishmana and sandfly classification and their synonymies, proposing an updated classification for each species of Leishmania and sandfly. We update information on the current distribution and dispersion of different species of Leishmania (53), sandflies (more than 800 at genus or subgenus level), and animal reservoirs in each of the following geographical ecozones: Palearctic, Nearctic, Neotropic, Afrotropical, Oriental, Malagasy, and Australian. We propose an updated list of the potential and proven sandfly vectors for each Leishmania species in the Old and New World. Finally, we address a classical question about digenetic Leishmania evolution: which was the first host, a vertebrate or an invertebrate? Conclusions and Significance We propose an updated view of events that have played important roles in the geographical dispersion of sandflies, in relation to both the Leishmania species they transmit and the animal reservoirs of the parasites.

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Journal

Journal ID (nlm-ta): Mar Drugs

Journal ID (iso-abbrev): Mar Drugs

Journal ID (publisher-id): marinedrugs

Title: Marine Drugs

Publisher: MDPI

ISSN (Electronic): 1660-3397

Publication date (Electronic): 10 October 2018

Publication date Collection: October 2018

Volume: 16

Issue: 10

Electronic Location Identifier: 376

Affiliations

[1 ]Department of Chemistry, University of South Florida, Tampa, FL 33620, USA; dhdemers@ 123456mail.usf.edu (D.H.D.); m.a.knestrick@ 123456gmail.com (M.A.K.)

[2 ]Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA; rfleeman@ 123456utexas.edu (R.F.); rtawfik@ 123456mail.usf.edu (R.T.); shaw@ 123456usf.edu (L.N.S.)

[3 ]Department of Global Health, University of South Florida, Tampa, FL 33613, USA; aazhari@ 123456kau.edu.sa (A.A.); asouza@ 123456taskforce.org (A.S.); bvesely@ 123456health.usf.edu (B.V.); Christopher.Rice@ 123456uga.edu (C.A.R.); DENNIS.KYLE@ 123456uga.edu (D.E.K.)

[4 ]Division of Immunity and Pathogenesis, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL 32827, USA; Mandy.Netherton@ 123456ucf.edu (M.N.); Rashmi.Gupta@ 123456ucf.edu (R.G.); Kyle.Rohde@ 123456ucf.edu (K.H.R.)

[5 ]Department of Molecular Medicine, University of South Florida, Tampa, FL 33613, USA; Beatrice.Colon@ 123456uga.edu

[6 ]Instituto Politécnico Nacional, Centro de Biotecnología Genómica, Blvd. del Maestro esq. Elías Piña s/n. Reynosa 88710, Tamaulipas, Mexico; mrodriguez@ 123456ipn.mx

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[* ]Correspondence: bjbaker@ 123456usf.edu

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Christopher A. Rice https://orcid.org/0000-0003-0672-9604

Bill J. Baker https://orcid.org/0000-0003-3033-5779

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Publisher ID: marinedrugs-16-00376

DOI: 10.3390/md16100376

PMC ID: 6212984

PubMed ID: 30308948

SO-VID: 3a095b87-e2ae-43f6-95ab-db30efdf2e2c

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Exploitation of Mangrove Endophytic Fungi for Infectious Disease Drug Discovery

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Drug Repurposing

Most cited references 39

Regulation of fungal secondary metabolism.

Big effects from small changes: possible ways to explore nature's chemical diversity.

A Historical Overview of the Classification, Evolution, and Dispersion of Leishmania Parasites and Sandflies

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