Table 2.

Comparison between different microbial host systems for production of recombinant proteins and natural products.

Microbial hosts	Advantages	Disadvantages	Compounds	References
Gram-negative Escherichia coli
	simple • Fast growth simple • Simple culture procedures simple • Cost-effective simple • High versatility of the enterobacterium and its associated systems	simple • Lack of post-translational modifications (PTMs) simple • Risk of translational errors due to the presence of a large number of rare codons simple • Expensive and often challenging purification process	simple • Recombinant human insulin simple • Artemisinin simple • Erythromycin A simple • Somatrem simple • Somatropin simple • Pegloticase simple • Insulin glargine simple • Pneumococcal vaccines simple • Filgrastim simple • Pegfilgrastim simple • Human serum albumin simple • Hepatitis B virus immunization simple • IFN α-2b simple • IL-6	Johnson, 1983; Abdin et al., 2003; Chang et al., 2007; Zhang et al., 2010; Ferrer-Miralles and Villaverde, 2013; Baeshen et al., 2015; Jozala et al., 2016; Sanchez-Garcia et al., 2016
Gram-positive Lactococcus lactis
	simple • Simplified downstream purification processes simple • Absence of endotoxins or unwanted glycosylation of proteins simple • Generally recognized as safe (GRAS) simple • Lack of secreted heterologous proteins degradation simple • Nisin-controlled gene expression system simple • Heterologous protein delivery in foodstuff or in the digestive tract	simple • Per liter secretion generally less robust than Bacillus sp. simple • AT-rich codon usage and/or the distribution of rare codons	simple • Nisin A simple • Pfs48/45 simple • Enterocin A simple • Pediocin PA-1 simple • IL-2 simple • IL-6 simple • Peanut allergen simple • Tetanus toxin fragment C simple • Transforming growth factor-β1	Steidler et al., 1998; Drouault et al., 2000; Martínez et al., 2000; Le Loir et al., 2005; Mierau and Kleerebezem, 2005; Glenting et al., 2007; Morello et al., 2008; Li and Vederas, 2009; Linares et al., 2010; Gyawali and Ibrahim, 2014; Bermúdez-Humarán et al., 2015; Li et al., 2015; Song et al., 2017
Streptomyces sp.	simple • Rapid growth simple • Abundant supply of secondary metabolite precursors simple • Ability to produce natural products. simple • Efficient protein secretion system such as Sec pathway and twin-arginine-translocation (Tat) pathway simple • Well-developed genetic manipulation	simple • Forms pellets or clumps simple • Low protein yield	simple • Streptomycin simple • Pikromycin simple • Kanamycin simple • Nystatin simple • Anthracyclines simple • Rapamycin simple • FK506 simple • Strepsesquitriol simple • Salinamides A and B simple • Cahuitamycin simple • Actinomycin D simple • Milbemycin simple • Mollemycin A simple • TNF α simple • hIL-10 simple • Streptokinase simple • IL-1β simple • IFN-α1 simple • Transforming growth factor-α simple • IL-2 simple • IFN-α2b simple • Tetracycline simple • Daptomycin simple • Chloramphenicol	Stanley and English, 1965; Kaslow et al., 1994; Trischman et al., 1994; Mann, 2001; Jung et al., 2006; Copping and Duke, 2007; Park et al., 2008, 2016; Vrancken and Anne, 2009; Fracchia et al., 2010; Anné et al., 2012; De Lima Procópio et al., 2012; Sanchez et al., 2012; Yang et al., 2013; Kim et al., 2015; Blunt et al., 2016; Jozala et al., 2016; Gao et al., 2017
Bacillus sp.	simple • Outstanding fermentation properties and protein production yield (20–25 g per liter) simple • Completely free toxin production simple • Flexibility for genetic engineering simple • Presence of proteome secretory pathway	simple • Primarily used in Enzyme production. simple • Plasmid instability simple • Presence of proteases: leads to difficulty in the production of recombinant proteins.	simple • Ieodoglucomide C simple • Ieodoglycolipid simple • Bacillomycin D and L simple • Alkaline cellulose simple • Alkaline protease simple • Alkaline α-amylase simple • hIL-3 simple • Fengycin simple • IL-1β simple • IFN-α2 simple • Staphylokinase simple • Iturins simple • Surfactin	Palva et al., 1983; Peypoux et al., 1984; Bellini et al., 1991; Kim et al., 2001; Westers et al., 2006; Deleu et al., 2008; Chang et al., 2011; Van Dijl and Hecker, 2013; Wang T. et al., 2015; El-Hossary et al., 2017
Fungi/yeast Saccharomyces cerevisiae
	simple • Fast growth rate simple • Technically practical simple • Cost-effective simple • Ability to generate post-translational modification as O-linked glycosylation, phosphorylation, acetylation, and acylation simple • Advanced fermentation science	simple • N-linked glycosylation patterns differ from higher eukaryotes simple • Lack some required precursor pathways simple • Codon usage is biased toward A + T	simple • Human serum albumin simple • Recombinant human insulin simple • Hepatitis B virus immunization simple • Artemisinic acid simple • Paclitaxel simple • hIL-6 simple • Insulin aspart simple • Pfs25 simple • Sapogenin simple • Saponin	McAleer et al., 1984; Guisez et al., 1991; Kaslow et al., 1994; Ballance, 1999; Ferrer-Miralles et al., 2009; Nielsen, 2013; Paddon et al., 2013; Baeshen et al., 2014; Ding et al., 2014; Meehl and Stadheim, 2014; Moses et al., 2014; Kung et al., 2018; Nandy and Srivastava, 2018
Aspergillus sp.	simple • GRAS status simple • Tolerate extreme cultivation conditions simple • Degrade and utilize diverse biopolymers, allowing cultivation on renewable resources simple • Major Source of citric acid production	simple • Production of mycotoxins (alpha toxins) simple • Many host proteases simple • Freely dispersed filaments or highly compact pellets formed during submerged fermentations	simple • Immunoglobulin G1(κ) simple • Antibodies and Fab′ fragment simple • Bicoumanigrin simple • Aspernigrin B simple • Lactoferrin simple • Enniatin simple • Human IL-2 simple • Human IL-6 simple • Phytase simple • L-asparaginase simple • Lovastatin simple • Tryptostatin B	Gaffar and Shethna, 1977; Carrez et al., 1990; Hiort et al., 2004; Papagianni, 2004; Ward et al., 2004; Grimm et al., 2005; Maheshwari, 2006; Pel et al., 2007; Maiya et al., 2009; Meyer et al., 2011; Cragg and Newman, 2013
Hansenula polymorpha	simple • GRAS status simple • Combined genetic manipulations, low cost screening. simple • Efficient fermentation properties, and protein modification simple • Ability to use and grow on methanol, glucose, or glycerol as its primary carbon sources simple • Thermo-tolerant	simple • The use of methanol creates hazardous conditions in lab use simple • Hyperglycosylation of heterologous products simple • Can lead to production instabilities due to sequence repetition on vector.	simple • IFNα-2a simple • Phytase simple • IL-6 simple • Human serum albumin simple • Human hemoglobin simple • HBV L-protein simple • Hepatitis B surface antigen	Janowicz et al., 1991; Gellissen et al., 1992; Hollenberg and Gellissen, 1997; Cox et al., 2000; Heijtink et al., 2002; Müller et al., 2002; Böer et al., 2007; Kunze et al., 2009; Celik and Calik, 2012