Editorial: Engineering the Microbial Platform for the Production of Biologics and Small-Molecule Medicines

Abstract

Editorial on the Research Topic Engineering the Microbial Platform for the Production of Biologics and Small-Molecule Medicines Microorganisms are the prominent sources of valuable products ranging from large (e.g., proteins, carbohydrate polymers, nucleic acids, even cells) to small molecules (e.g., microbial metabolites, signaling molecules, growth factors, etc.). Most of these small molecules termed as “secondary metabolites (SM)s” are inessential to the producer for their growth and development. However, these SMs have significant applications in human and animal health (Demain, 2000; Bhan et al., 2013; Wang et al., 2016; Dhakal and Sohng, 2017). Besides, several biologics pharmaceutical ingredients extracted from animals, plants, and microorganisms such as antibodies, vaccines, receptor modulators or replacement/modulators of enzymes are applied for human welfare (Kinch, 2005; Lacana et al., 2007). The host microorganisms engineered for the production of such small molecular medicines or relatively complex biologics are termed as “microbial cell factories (MCF).” Recently, metabolic engineering approaches are developed for engineering of metabolism and biosynthetic pathways in these MCFs for better performance (Davy et al., 2017; Choi et al., 2018). The papers published in this Research Topic have attempted to explore the current state of the art of microbial engineering along with its diverse approaches. Pham et al. have summarized the biological activities and applications of a variety of small molecular medicines and biologics. The manuscript has reviewed the diverse microbial systems used for the production of these biomolecules along with the versatile engineering strategies of such microbial platforms. Generally, each of the microbial strains can produce multiple compounds, but it can produce only subsets of these compounds under specific growth conditions. Therefore, variations in cultivation parameters can elicit the production and discovery of new SMs. For example, by changing cultivation parameters such as temperature, salinity, aeration, and even by altering the shape of the flasks, the production profile from a microbial platform can be altered (Bode et al., 2002). Pan et al. have provided comprehensive information regarding the exploration of structural diversity of microbe secondary metabolites using one strain many compounds (OSMAC) approach. They have presented the role of variation in medium, cultivation conditions, use of epigenetic modifiers, and co-cultivation in the discovery of novel secondary metabolites from diverse microbial sources utilizing OSMAC approach (Pan et al.). Escherichia coli is reported as the most common cell factory for the production of both small molecules and biologics. The clear understanding of its physiological and genetic characteristics, fast-growth even in minimal salts medium, and availability of easy genetic manipulation techniques has established it as first-choice production host (Liu et al., 2015). Also, systems metabolic engineering approaches that combine knowledge of systems biology, synthetic biology, and evolutionary engineering into the traditional metabolic engineering, has facilitated the development of E. coli as a robust production host for heterologous expression of small molecules and complex biologics (Choi et al., 2019). So, different metabolic engineering approaches utilizing E. coli as microbial platform have been presented in this Research Topic. Wang et al. have reviewed different aspects of terpenoid production using E. coli including the metabolic engineering and genome engineering approaches. Li et al. utilized product resistance and targeted metabolic engineering for the production of equol in E. coli. Similarly, the combination of product tolerance, evolution engineering, and modular co-culture was utilized for the production of pinene (Niu et al.). The metabolic engineering approach utilizing gene over-expression cassette for enhanced production of nucleotide diphosphate (NDP)-sugars was utilized for generating the salicylate glucoside and other glycosylated variants (Qi et al.). Similarly, the gene-silencing approach was employed for enriching the titer of 3′-phosphoadenosine-5′-phosphosulfate (PAPS), which is donor substrate for sulfation of natural product (NP) precursors. Hence, by inhibiting the degradation of PAPS mediated by repression of PAPS reductase (cysH) and optimization of different sulfate donors significantly enhanced the production titer of naringenin-7-sulfate (Chu et al.). Ribosomally synthesized and post-translationally modified peptides (RiPPs) are special class of NPs with diverse structures and bioactivities, and thus possess a complex biosynthetic mechanism. Different aspects for heterologous expression of RiPPs in E. coli have been reviewed by Zhang et al. Due to the presence of endotoxins in products obtained from Gram negative bacteria as E. coli, some of the non-lethal Gram-positive bacteria including the native producer strains such as actinobacteria or heterologous hosts [generally recognized as safe (GRAS)] such as Bacillus and Corynebacterium are used as excellent cell factories in industries. Actinobacteria are characterized as the most prominent producers of thousands of bioactive molecules, particularly small molecular medicines such as commercially available antibiotics and anticancer-drugs (Dhakal et al., 2017; Rangseekaew and Pathom-aree, 2019). In some cases, NPs from these actinomycetes are cryptic or not produced in a significant amount. Thus, precise metabolic engineering can be employed in a native host or genetically tractable alternative heterologous hosts for significant production. Li et al. performed whole genome sequencing of the producer strain, analyzed the genome data by computational tools and isolated...