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

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Review

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

Janette V Pham et al. Front Microbiol.

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.

Keywords: biological activity; biologics; combinatorial biosynthesis; genetic engineering; microbial cell factories; natural products; production improvement.

Figures

FIGURE 1
FIGURE 1
Structures of natural products with antibiotic activity.
FIGURE 2
FIGURE 2
Structures of natural products with (A) antifungal and (B) anticancer/antitumor activities.
FIGURE 3
FIGURE 3
Structures of natural products with (A) immunosuppressive/anti-inflammatory, (B) biofilm-inhibitory, and (C) other activities.
FIGURE 4
FIGURE 4
Crystal structures of (A) recombinant human insulin (Humulin®) (PDB 4F0N) (Favero-Retto et al., 2013); (B) interferon (IFN) α-2b (PDB 3SE3) (Thomas et al., 2011); (C) granulocyte colony growth factor pegfilgrastim (Neupeg®) (PDB 1HRG) (Hill et al., 1993); (D) human interleukin-3 (PDB 5UV8) (Broughton et al., 2018); and (E) human serum albumin (Recombumin®and Albucult®) (PDB 1AO6) (Sugio et al., 1999). The models are colored according to the sequence by a rainbow color from the N-terminus (blue) to the C-terminus (red).
FIGURE 5
FIGURE 5
An overview of multiple strategies of product improvements and generation of new analogs.

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