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      A Review of the Microbial Production of Bioactive Natural Products and Biologics

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          Abstract

          A variety of organisms, such as bacteria, fungi, and plants, produce secondary metabolites, also known as natural products. Natural products have been a prolific source and an inspiration for numerous medical agents with widely divergent chemical structures and biological activities, including antimicrobial, immunosuppressive, anticancer, and anti-inflammatory activities, many of which have been developed as treatments and have potential therapeutic applications for human diseases. Aside from natural products, the recent development of recombinant DNA technology has sparked the development of a wide array of biopharmaceutical products, such as recombinant proteins, offering significant advances in treating a broad spectrum of medical illnesses and conditions. Herein, we will introduce the structures and diverse biological activities of natural products and recombinant proteins that have been exploited as valuable molecules in medicine, agriculture and insect control. In addition, we will explore past and ongoing efforts along with achievements in the development of robust and promising microorganisms as cell factories to produce biologically active molecules. Furthermore, we will review multi-disciplinary and comprehensive engineering approaches directed at improving yields of microbial production of natural products and proteins and generating novel molecules. Throughout this article, we will suggest ways in which microbial-derived biologically active molecular entities and their analogs could continue to inspire the development of new therapeutic agents in academia and industry.

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          Most cited references258

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          Assembly-line enzymology for polyketide and nonribosomal Peptide antibiotics: logic, machinery, and mechanisms.

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            Bacillus thuringiensis and its pesticidal crystal proteins.

            During the past decade the pesticidal bacterium Bacillus thuringiensis has been the subject of intensive research. These efforts have yielded considerable data about the complex relationships between the structure, mechanism of action, and genetics of the organism's pesticidal crystal proteins, and a coherent picture of these relationships is beginning to emerge. Other studies have focused on the ecological role of the B. thuringiensis crystal proteins, their performance in agricultural and other natural settings, and the evolution of resistance mechanisms in target pests. Armed with this knowledge base and with the tools of modern biotechnology, researchers are now reporting promising results in engineering more-useful toxins and formulations, in creating transgenic plants that express pesticidal activity, and in constructing integrated management strategies to insure that these products are utilized with maximum efficiency and benefit.
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              Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle.

              A streptomycete was isolated from an Easter Island soil sample and found to inhibit Candida albicans, Microsporum gypseum and Trichophyton granulosum. The antibiotic-producing microorganism was characterized and identified as Streptomyces hygroscopicus. The antifungal principle was extracted with organic solvent from the mycelium, isolated in crystalline form and named rapamycin. Rapamycin is mainly active against Candida albicans; minimum inhibitory concentration against ten strains ranged from 0.02 to 0.2 mug/ml. Its apparent activity against Microsporum gypseum and Trichophyton granulosum is lower because of its instability in culture media on prolonged incubation required by these fungi. No activity was observed against gram-positive and gram-negative bacteria. Acute toxicity in mice is low.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                20 June 2019
                2019
                : 10
                : 1404
                Affiliations
                [1] 1Geisinger Commonwealth School of Medicine , Scranton, PA, United States
                [2] 2Baruch S. Blumberg Institute , Doylestown, PA, United States
                [3] 3Department of Chemistry and Nanoscience, Ewha Womans University , Seoul, South Korea
                [4] 4School of Life Sciences and Biotechnology, Kyungpook National University , Daegu, South Korea
                [5] 5Natural Products Discovery Institute , Doylestown, PA, United States
                Author notes

                Edited by: Dipesh Dhakal, Sun Moon University, South Korea

                Reviewed by: Alejandra Prieto-Davó, Universidad Nacional Autónoma de México, Mexico; Yousong Ding, University of Florida, United States

                This article was submitted to Microbial Physiology and Metabolism, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2019.01404
                6596283
                31281299
                d844aa33-1fe6-40fc-acac-3ddda4fcb0d6
                Copyright © 2019 Pham, Yilma, Feliz, Majid, Maffetone, Walker, Kim, Cho, Reynolds, Song, Park and Yoon.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 January 2019
                : 04 June 2019
                Page count
                Figures: 5, Tables: 2, Equations: 0, References: 291, Pages: 27, Words: 0
                Funding
                Funded by: National Research Foundation of Korea 10.13039/501100003725
                Funded by: Centre of Excellence for Biosecurity Risk Analysis 10.13039/501100009311
                Funded by: Korea Institute of Marine Science and Technology promotion 10.13039/501100011705
                Categories
                Microbiology
                Review

                Microbiology & Virology
                natural products,biologics,biological activity,microbial cell factories,genetic engineering,combinatorial biosynthesis,production improvement

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