Cover
1 Biochemical Aspects of Microbial Product Synthesis: a Relook
1. 1.1 Introduction
2. 1.2 History of Industrial Production of Microbial Products
3. 1.3 Conclusion
4. Acknowledgments
5. References
2 Cellular Events of Microbial Production: Important Findings So Far
1. 2.1 Introduction
2. 2.2 Microbial Metabolism and Evolution of Metabolic Pathways
3. 2.3 Microbial Fermentation
4. 2.4 The Microbial Cellular Events
5. 2.5 Cell Signalling in Microorganisms
6. 2.6 Microbial Performance Under Stress Conditions
7. Acknowledgment
8. References
3 Microbial Metabolism in a Refined Carbon Source: Generalities
1. 3.1 Introduction
2. 3.2 Microbial Metabolism in Presence of Pure and Crude Substrate
3. 3.3 Microbial Metabolism in Presence of Pure and Mixed Cultures
4. 3.4 Microbial Metabolism in the Presence of Co‐Substrate
5. 3.5 Microbial Metabolism in the Presence of Input Parameters
6. 3.6 Microbial Metabolism in the Presence of Varying Fermentation Conditions
7. 3.7 Pros and Cons of Refined Substrate for Metabolic Metabolisms
8. 3.8 Conclusions
9. Acknowledgment
10. References
4 Non‐refined Carbon Sources and Microbial Performance
1. 4.1 Introduction
2. 4.2 Non‐refined Carbon Sources: a Brief Account
3. 4.3 Microbial Assimilation of Non‐Refined Carbon Sources
4. 4.4 Microbial Sensing to Non‐Refined Carbon Sources
5. 4.5 Guiding Product Outcomes via Rewiring of Cellular Regulatory Circuit
6. 4.6 Conclusions
7. References
5 Cellular versus Biochemical Control over Microbial Products
1. 5.1 Introduction
2. 5.2 3‐Hydroxy‐propionic Acid
3. 5.3 Fumaric Acid
4. 5.4 Itaconic Acid
5. 5.5 Glucaric Acid
6. 5.6 Butanol
7. 5.7 Malic Acid
8. 5.8 Gluconic Acid
9. 5.9 Aminovalaric Acid
10. 5.10 Glutamic Acid
11. 5.11 Cadaverine (1,5‐diaminopentane)
12. 5.12 Conclusion
13. Acknowledgment
14. References
6 Pre‐Treatment of Alternative Carbon Source: How Does it Make Sense to Microorganism at Cellular Level?
1. 6.1 Introduction
2. 6.2 Pre‐Treated Carbon Source and Microbial Assimilation: Cellular and Biochemical Aspects
3. 6.3 Challenges of Inhibitory Hydrolysis Products and Strategic Solution
4. 6.4 Conclusion
5. Acknowledgments
6. References
7 Microbial Metabolic Pathways in the Production of Valued‐added Products
1. 7.1 Introduction
2. 7.2 Microbial Molecular Structure
3. 7.3 Biomass Production
4. 7.4 Enzymes
5. 7.5 Biofuels
6. 7.6 Alkaloids, Terpenoids, Polyketides and Flavonoids
7. 7.7 Organic Acids
8. 7.8 Rare Sugars
9. 7.9 Conclusions
10. References
8 Communication for a Collective Response to Environmental Stress
1. 8.1 Introduction
2. 8.2 Quorum Sensing in Bacteria and the Related Phenotypes
3. 8.3 Fermentation and Quorum Sensing in Bacteria
4. 8.4 Quorum Sensing in Fungi and the Related Phenotypes
5. 8.5 Fermentation and Quorum Sensing in Fungi
6. 8.6 Quorum Sensing in Bacteria and Fungi: Similarities and Differences
7. Acknowledgment
8. References
9 Biochemical and Cellular Events in Controlling Microbial Performance
1. 9.1 Biochemical vs. Molecular Cues for Microbial Performances
2. 9.2 Sequential Evidences of Biochemical and Molecular Controlling Over Microbial Performances
3. 9.3 Biochemically Influenced Molecular Events and Vice Versa
4. 9.4 Facts at the Interface of Biochemical and Molecular Controlling: Products vs Applied Parameters
5. 9.5 Conclusions
6. References
10 Qualitative vs. Quantitative Control Over Microbial Products
1. 10.1 Introduction
2. 10.2 Qualitative vs. Quantitative Control Over Microbial Products/Fungal Products
3. 10.3 Fungal Morphology and Product Spectrum: a Representative Theme
4. 10.4 Effectiveness of Qualitative Domain for Different Microorganisms
5. 10.5 Emphasizing the Need: Qualitative and Quantitative Importance
6. 10.6 Conclusions
7. References
11 Microbes and Their Products as Sensors in Industrially Important Fermentations
1. 11.1 Introduction
2. 11.2 Sensors
3. 11.3 Transducers in Conjunction With Microbe Sensors
4. 11.4 Metabolite Measuring Systems
5. 11.5 Other Measuring Systems
6. 11.6 Applications of Microbe Sensors in Some Commercially Important Products
7. 11.7 Conclusions
8. References
12 Practical Aspects and Case Studies of Industrial Scale Fermentation
1. 12.1 Introduction
2. 12.2 Scale Up Challenges
3. 12.3 Microbial Tolerance
4. 12.4 Phage Invasion
5. 12.5 Process Failures
6. 12.6 Potent Inhibitors (e.g. Substrate Inhibition)
7. 12.7 Case Studies: Biofuels (Biodiesel, Ethanol) Enzymes (Novozymes), Antibiotics, Platform Chemicals
8. 12.8 Conclusions
9. Acknowledgments
10. References
13 Future Market and Policy Initiatives of New High Value Products
1. 13.1 Introduction
2. 13.2 Market Analysis, Market Trends and Statistics
3. 13.3 Public Mobilization Initiatives and Government Policies
4. 13.4 Regulations and Conformity – Case of Biofuels
5. 13.5 Global Marketing and Competitiveness in Biofuel Sector
6. References
Index
End User License Agreement

List of Tables

Chapter 02
1. Table 2.1 Overview of two classes of fermentative microorganisms.
2. Table 2.2 Response and adaptation of Saccharomyces cerevisiae to major stresses.
Chapter 03
1. Table 3.1 For the glycerol fermentation in the process of hydrogen production.
2. Table 3.2 Increased production across the pure and mixed‐culture system under different operating conditions.
3. Table 3.3 The important details of the co‐substrates studies during fermentation.
4. Table 3.4 Different fermentation conditions carried out to increase final output.
Chapter 06
1. Table 6.1 Various lignocellulosic waste investigated for butanol production and the corresponding concentration of butanol produced and duration of fermentation (Adapted from Jang et al., 2012).
2. Table 6.2 Various pre‐treatment effects on inhibitors produced by different lignocellulosic biomass and discussion on possible solution/conclusion.
3. Table 6.3 Detoxification studies on various lignocellulosic biomass and their effect on inhibitor removal formed during pre‐treatment step.
Chapter 07
1. Table 7.1 Synthetic and alternative carbon sources used in the formation of different microbial‐derived products.
Chapter 08
1. Table 8.1 Different Quorum Sensing Systems and influential environmental cues in bacteria and their associated phenotypes.
2. Table 8.2 Different Quorum Sensing Systems in fungi and their associated phenotypes.
Chapter 09
1. Table 9.1 Evidences of biochemical and molecular controlling and its direct or indirect effects on microbial performances.
2. Table 9.2 Evidences for biochemically influenced molecular events and vice versa and the final benefit
Chapter 10
1. Table 10.1 Qualitative assay for determination of enzymes.
2. Table 10.2 Solid substrates used for fermentation.
3. Table 10.3 Example of microbial product and process.
4. Table 10.4 Fungal product spectrum*.
Chapter 11
1. Table 11.1 A list of the sensors and their applications in the fermentation industry.
Chapter 13
1. Table 13.1 Bio‐surfactant market: total production volume and income
2. Table 13.2 Enzymes market based on total production volume
3. Table 13.3 Regional market of enzymes

List of Illustrations

Chapter 01
1. Figure 1.1 Production of lactic acid by microbial fermentation and its derivatives.
2. Figure 1.2 Microbial sensing classification according to signal origin.
Chapter 03
1. Figure 3.1 The metabolic pathway of glycerol fermentation during biofuels production.
Chapter 04
1. Figure 4.1 Schematic of utilization pathways for various non‐refined carbon sources. Operation of multiple pathways simultaneously for several substrates would allow the cell to accumulate precursors such as NAD(P)H and Acetyl CoA for channelling to different products. PPP, Pentose Phosphate Pathway; EDP, Entner‐Doudoroff Pathway. Rounded rectangles indicate feedstock while ellipses indicate fermentation products.
2. Figure 4.2 Mechanism of substrate prioritization in microbial metabolism. (a) Dephosphorylation of PTS component EIIA upon entry of glucose and/or other PTS sugars causes inhibition of transport of non‐PTS sugars via CCR. (b) For xylose/arabinose mixtures, binding of arabinose to its regulator AraC displaces xylose regulator XylR from promoter for xylose utilization genes (xyl) thereby leading to repression in gene expression and impaired xylose utilization. PTS, Phosphotransferase system; XylE, xylose‐proton symporter; XylFGH, xylose ABC transporter; AraE, arabinose‐proton symporter; AraFGH, arabinose ABC transporter; A, arabinose.
Chapter 05
1. Figure 5.1 Genetically engineered metabolic pathway for the production of 3‐hydroxy‐propionic acid in E. coli.
2. Figure 5.2 Genetically engineered metabolic pathway for the production of fumaric acid in E. coli.
3. Figure 5.3 Genetically engineered metabolic pathway for the production of itaconic acid in E. coli.
4. Figure 5.4 Genetically engineered metabolic pathway for the production of glucaric acid in E. coli.
5. Figure 5.5 Genetically engineered metabolic pathway for the production of butanol in E. coli.
6. Figure 5.6 Genetically engineered metabolic pathway for the production of malic acid in E. coli.
7. Figure 5.7 Genetically engineered metabolic pathway for the production of gluconic acid in E. coli.
8. Figure 5.8 Genetically engineered metabolic pathway for the production of 5‐aminovalerate in E. coli.
9. Figure 5.9 Genetically engineered metabolic pathway for the production of glutamic acid in E. coli.
10. Figure 5.10 Genetically engineered metabolic pathway for the production of cadaverine in E. coli.
Chapter 06
1. Figure 6.1 Conversion of lignocellulose to fuels and chemicals.
2. Figure 6.2 Production chemicals from lignocellulosic biomass.
3. Figure 6.3 Glycolytic or Embden‐Meyerhof‐Parnas pathway.
4. Figure 6.4 TCA or Krebs cycle.
5. Figure 6.5 Pathway of pentose sugar utilization.
6. Figure 6.6 Target enzymes for increasing bioethanol production (Danner and Braun, 1999).
7. Figure 6.7 Metabolic pathway of butanol synthesis.
8. Figure 6.8 Metabolic pathway of glucose during dark fermentation (Xia et al., 2015).
9. Figure 6.9 Conversion of biomass to methane.
10. Figure 6.10 Illustration of glycolysis in E. coli.
11. Figure 6.11 Pentose sugar utilization and lactic acid synthesis in lactic acid bacteria.
Chapter 07
1. Figure 7.1 Chemical elements and their relative abundance in microbial cells.
2. Figure 7.2 General mechanism of lipid accumulation by oil‐producing microorganisms. AMPD = AMP deaminase; ICDH = isocitrate dehydrogenase; CMT = citrate–malate translocase; ACL = ATP citrate lyase; PFA = Polyunsaturated fatty acids; MDH = malate dehydrogenase.
3. Figure 7.3 Biosynthetic pathways of biofuels (G3P: glyceraldehyde 3 phosphate; DMAPP: dimethylallyl pyrophosphate; MEP: methylerythritol 4 phosphate; IPP: Isopentenyl pyrophosphate; MVA: mevalonate; FFAs: free fatty acids; FAEEs: fatty acid ethyl esters; FAMEs: fatty acid methyl esters).
Chapter 08
1. Figure 8.1 Chemical structures of common Quorum Sensing Molecules (QSM) produced by bacteria, involved in modulating phenotypes shown in Table 8.1.
2. Figure 8.2 Schematic overview of butanediol and mixed acid fermentation in Enterobacteriaceae.
3. Figure 8.3 Schematic overview of Ehrlich pathway.
Chapter 09
1. Figure 9.1 Schematic representation of biochemical and molecular events which can be explored for controlling or manipulating microbial performances.
Chapter 10
1. Figure 10.1 Screening of pigment producers.
2. Figure 10.2 Screening of citric acid producers.
3. Figure 10.3 Screening of organic acid producers.
4. Figure 10.4 Screening of antimicrobial agent producers – Agar Disc diffusion method.
5. Figure 10.5 Screening of antimicrobial agent producers – Agar well diffusion method.
6. Figure 10.6 Screening of antimicrobial agent producers – Agar plug diffusion method.
7. Figure 10.7 Screening of antagonistic agent producers – Cross streak method.
8. Figure 10.8 Fungi morphology: hyphal elements.
Chapter 11
1. Figure 11.1 Principle of the Oxygen Sensor based on the respiration activity.
2. Figure 11.2 Principle of the Oxygen Sensor based on the Electron Transfer Measuring Systems.
3. Figure 11.3 The metabolites produced by the microbes can also use as sensors.
4. Figure 11.4 Application of microbe sensor in the quality control of red wine.
5. Figure 11.5 The regulation, construction and organization of the Genetically engineered microbial whole‐cell biosensors.
Chapter 12
1. Figure 12.1 General schemes of bioprocess stages.
2. Figure 12.2 Flow diagram of Biodiesel production.
Chapter 13
1. Figure 13.1 Main bioethanol producers in the world.
2. Figure 13.2 Main biodiesel producers and total world production.
3. Figure 13.3 Evolution of biofuels production. Source: (EIA, 2016).
4. Figure 13.4 Most used bio‐surfactants by kind of molecule.
5. Figure 13.5 Consumption of bio‐surfactants according to segment of applications.

List of Contributors

Aishvarya Agrawal
Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, India

Shadab Ahmed
Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, India

Devangana Bhuyan
TERI Deakin Nanobiotechnology Centre, Biotechnology and Management of Bioresources Division, The Energy and Resources Institute, Haryana, India

Jean François Blais
Institut national de la recherche scientifique, Centre ‐ Eau Terre Environnement, Québec(QC), Canada

Satinder Kaur Brar
Institut national de la recherche scientifique, Centre ‐ Eau Terre Environnement, Québec, Canada

Ratul Kumar Das
TERI‐Deakin Nanobiotechnology Centre, Biotechnology and Management of Bioresources Division, The Energy and Resources Institute, Haryana, India

Satya Eswari
Department of Biotechnology, National Institute of Technology, Raipur, Chhattisgarh, India

Ana M. Finco
Bioprocess Engineering and Biotechnology Department, Federal University of Paraná, Curitiba, Brazil

G. Gallastegui
Department of Chemical and Environmental Engineering, Faculty of Engineering Vitoria‐Gasteiz, University of the Basque Country (UPV/EHU), Spain

Rosa Galvez‐Cloutier
Université Laval, Department of Civil Engineering and Water Engineering, Quebec, Canada

Rachna Goswami
Biosciences Department, Rajiv Gandhi University of Knowledge Technologies, India

Tayssir Guedri
Institut national de la recherche scientifique, Centre ‐ Eau Terre Environnement, Québec(QC), Canada

Krishnamoorthy Hegde
INRS‐ETE, Université du Québec, Québec, Canada

Michele Heitz
Université de Sherbrooke, Canada

Susan Grace Karp
Bioprocess Engineering and Biotechnology Department, Federal University of Paraná, Curitiba, Brazil

Guneet Kaur
School of Energy and Environment, City University of Hong Kong, Kowloon Tong, Hong Kong

Azadeh Kermanshahi pour
Biorefining and Remediation Laboratory, Department of Process Engineering and Applied Science, Dalhousie University, Halifax, Canada

Preetika Rajeev Kuknur
Institut national de la recherche scientifique, Centre ‐ Eau Terre Environnement, Québec, Canada

Pratik Kumar
INRS‐ETE, Université du Québec, Québec, Canada

A. Larrañaga
Department of Mining‐Metallurgy Engineering and Materials Science & POLYMAT, Faculty of Engineering of Bilbao, University of the Basque Country (UPV/EHU), Spain

Luiz A. J. Letti
Bioprocess Engineering and Biotechnology Department, Federal University of Paraná, Curitiba, Brazil

Sara Magdouli
Institut national de la recherche scientifique, Centre ‐ Eau Terre Environnement, Québec, Canada

Vijay Kumar Mishra
Biosciences Department, Rajiv Gandhi University of Knowledge Technologies, India

Somnath Nandi
Department of Technology, Savitribai Phule Pune University, Pune, India

Shreyas Niphadkar
Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, India

Juliana de Oliveira
Bioprocess Engineering and Biotechnology Department, Federal University of Paraná, Curitiba, Brazil

Carlos S. Osorio‐González
Institut national de la recherche scientifique, Centre ‐ Eau Terre Environnement, Québec, Canada

Vinayak Laxman Pachapur
Institut national de la recherche scientifique, Centre ‐ Eau Terre Environnement, Québec, Canada; Université Laval, Department of Civil Engineering and Water Engineering, Quebec, Canada

Maria G. B. Pagnoncelli
Bioprocess Engineering and Biotechnology Department, Federal University of Technology ‐ Paraná (UTFPR), Dois Vizinhos, Brazil

Vishal Pandey
Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, India

Gilberto V. de Melo Pereira
Bioprocess Engineering and Biotechnology Department, Federal University of Paraná, Curitiba, Brazil

Thi Than Ha Pham
Centre National en Électrochimie et en Technologies Environnementales, Shawinigan, Québec, Canada; Université de Sherbrooke, Sherbrooke, Québec, Canada

Ha Thi Thanh Pham
Université de Sherbrooke Canada; Centre National en Électrochimie et en Technologies Environnementales, Shawinigan, Québec, Canada

Radhika Pilli
Microbiology department, Bharathiar University, Coimbatore, TN, India

Maria Puig‐Gamero
Universidad de Castilla La Mancha, Spain

Antonio Avalos Ramirez
Centre National en Électrochimie et en Technologies Environnementales, Shawinigan, Québec, Canada

Keyur Raval
Department of Chemical Engineering, National Institute of Technology, Surathkal, Karnataka, India

Ritu Raval
Department of Biotechnology, Manipal Institute of Technology, Manipal, Karnataka, India

Thana Saffar
Université du Québec en Abitibi‐Témiscamingue, Rouyn‐Noranda (Québec), Canada

Paula Sánchez
Universidad de Castilla La Mancha, Spain

Luz Sanchez‐Silva
Universidad de Castilla La Mancha, Spain

Joseph Sebastian
INRS‐ETE, Université du Québec, Québec, Canada

Aishwarya Shankapal
Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, India

Carlos Ricardo Soccol
Bioprocess Engineering and Biotechnology Department, Federal University of Paraná, Curitiba, Brazil

Vanete Thomaz Soccol
Bioprocess Engineering and Biotechnology Department, Federal University of Paraná, Curitiba, Brazil

Rouissi Tarek
Institut national de la recherche scientifique, Centre ‐ Eau Terre Environnement, Québec, Canada

José Luis Valverde
Universidad de Castilla La Mancha, Spain

Mausam Verma
INRS‐ETE, Université du Québec, Québec, Canada

1
Biochemical Aspects of Microbial Product Synthesis: a Relook

G. Gallastegui¹, A. Larrañaga², Antonio Avalos Ramirez³, and Thi Than Ha Pham^3,4

¹ Department of Chemical and Environmental Engineering, Faculty of Engineering Vitoria‐Gasteiz, University of the Basque Country (UPV/EHU), Spain

² Department of Mining‐Metallurgy Engineering and Materials Science & POLYMAT, Faculty of Engineering of Bilbao, University of the Basque Country (UPV/EHU), Spain

³ Centre National en Électrochimie et en Technologies Environnementales, Shawinigan, Québec, Canada

⁴ Université de Sherbrooke, Sherbrooke, Québec, Canada

1.1 Introduction

Microbes are living unicellular or multicellular organisms (bacteria, archaea, most protozoa, and some fungi and algae) that must be greatly magnified to be seen. Despite their tiny size, they play an indispensable role for humanity and the health of ecosystems. For instance, until the discovery of an artificial nitrogen fixation process by the German chemists Fritz Haber and Carl Bosch in the first half of the 20^th century, some soil microbes on the roots of peas, beans, and a few other plants were the solely responsible for the nitrogen release necessary for plants growth (Hager, 2008). This invention allowed to feed billions more people than the earth could support otherwise.

Besides, humanity has exploited some of the vast microbial diversity like miniature chemical factories for thousands of years in the production of fermented foods and drinks, such as wine, beer, yogurt, cheese and bread. In fact, the use of yeast as the biocatalyst in foodstuffs making is thought to have begun around the Neolithic period (ca. 10 000‐4000 BCE), when early humans transitioned from hunter‐gatherers to living in permanent farming communities (Rasmussen, 2015). Vinegar, the first bio‐based chemical (not intended as a beverage) produced at a commercial scale was known, used and traded internationally before the time of the Roman Empire (Licht, 2014).

The staggering transformation undergone by biotechnology from serendipity and black‐box concepts to rational science and increasing understanding of biological systems has led to not only a direct influence of microbes on human lives, but the emergence of new industries that take advantage of these organisms in large‐scale processes devoted to the manufacture of high value‐added compounds, energy production and environmental protection. Nevertheless, scientists and engineers are still discovering the broad array of complex signalling that microorganisms have developed to ensure their survival in a wide range of environmental conditions, and making their utmost effort to direct them towards our own ends (Manzoni et al., 2016). In this chapter, a brief summary regarding the historical production of microbial products, their niche in the current global market and the importance of microbial sensing (and other new disciplines) to convert biological systems in industrially relevant actors is presented.

1.2 History of Industrial Production of Microbial Products

In the 1800s, Louis Pasteur (and later Eduard Buchner) proved that fermentation was the result of microbial activity and, consequently, the different types of fermentations were associated with different types of microorganisms. In more recent times (1928), Alexander Fleming understood that the Penicillium mould produces an antibacterial bio‐chemical (antibiotics discovery), which was extracted, isolated and named penicillin. Subsequent periods of conflicts (e.g., World Wars I and II) intensified the needs of the population and, at the same time, the creativity and inventiveness of scientists and engineers, who developed large‐scale fermentation techniques to make industrial quantities of drugs, such as penicillin, and biofuels, such as biobutanol and glycerol, giving rise to industrial biotechnology. In 1952, Austrian chemists at Biochemie (now Sandoz) developed the first acid‐stable form of penicillin (Penicillin V) suitable for oral‐administration and achieved an extraordinary success in the treatment of infections during World War II (Williams, 2013).

Biobutanol production is recognized as one of the oldest industrial‐scale fermentation processes. It was generated by anaerobic ABE (acetone–butanol–ethanol) fermentation of sugar extract using solventogenic clostridia strains, with a typical butanol:acetone:ethanol mass fraction ratio around 6:3:1. Until the 1920s, acetone was the most sought‐after bioproduct of commercial interest. An emerging automotive paint industry and the need of quick‐drying lacquers, such as butyl acetate, changed the economic landscape and by 1927 butanol displaced acetone as the target product (Rangaswamy et al., 2012). From 1945 to 1960, about two thirds of the butanol production in North America was based on the conventional ABE fermentation. Nevertheless, butanol yield by anaerobic fermentation remained sub‐optimal, and this biobased product was progressively replaced by low cost petrochemical production (Maiti et al., 2016).

When Watson and Crick (with the valuable help from Wilkins and Franklin) worked out the structure of DNA in 1953, they barely imagined that this latter discovery supposed a milestone in the development of modern industrial biotechnology. Thus, in the following decades traditional industrial biotechnology merged with molecular biology to yield more than 40 biopharmaceutical products, such as erythropoietin, human growth hormone and interferons (Demain, 2000). Since then, biotechnology has steadily developed and now plays a key role in several industrial sectors, such as industrial applications, food and beverages, nutritional and pharmaceuticals or plastics and fibers, providing both high value products and commodity products (Heux et al., 2015).

Although, as shown in the previous paragraphs, the use of microorganisms and enzymes for the production of essential items has a long history, the recent linguistic term “white biotechnology” has been assigned to the application of biotechnology for the processing and production of chemicals, materials and energy. It is based on microbial fermentation processes and it works with nature in order to maximize and optimize existing biochemical pathways that can be used in manufacturing. The development of cost effective fermentation processes has allowed industry to target previously abandoned fermentation products and new ones which used to be of small interest for the naphtha‐relying chemical industry, such as succinic acid or lactic acid. In the latter case, and although the chemical synthesis of lactic acid from petrochemical feedstock is more familiar to chemists, approximately 90% of its production is accomplished by microbial fermentation (Wang et al., 2015). Nowadays, this platform molecule is used as a building block for the synthesis of chemicals such as acrylic acid and esters (by catalytic dehydration), propylene glycol (by hydrogenolysis) and lactic acid esters (by esterification) (Figure 1.1).

Flow of lactic acid production by microbial fermentation and its derivatives from substrates to fermentation to lactic acid to catalytic distillation, esterification, hydrogenolysis, and catalytic dehydration. — **Figure 1.1** Production of lactic acid by microbial fermentation and its derivatives.

1.2.1 Advances of Biochemical Engineering and Their Effects on Global Market of Microbial Products

Economic viability of bio‐derived products, especially in the case of biofuels, has been traditionally limited to a large extent by the selection of cheap carbon‐rich raw materials as feedstock, applied production mode, downstream processing and the scarcity of naturally occurring microorganisms that are able to deliver the desired compounds at a high production‐rate. Conventional bio‐based products ultimately turned out so expensive to compete with petroleum‐derived chemicals that they were hardly worth producing.

Despite these drawbacks, advances in biotechnology in recent years have enabled the reengineering of the bioprocesses incorporating several transformation or purification steps into only one, reducing time and operating costs. This has involved the increase of bioprocesses yield, boosting production of biobased materials. Currently, biotechnology advances (microbial, enzymatic and biology engineering) can be considered among the new technological revolutions, having huge impacts in industry, society and economy, as nanotechnology‐materials, informatics and artificial intelligence.

Therefore, a resurgence in the production of fermentation chemicals including biofuels, chemical building blocks, such as organic acids, amino acids, alcohols (diols, thiols) and specialty chemicals, such as surfactants, thickeners, enzymes, antibiotics and fine chemicals (pigments, fragrances, etc.) is expected in the years to come. The global fermentation chemicals market was 51.83 ·10⁶ tons in 2013 and is expected to reach 70.76 ·10⁶ tons by 2020, growing at a Compound Annual Growth Rate (CAGR) of 4.5% from 2014 to 2020, with North America emerging as the leading regional market and accounting for 33.8% of total market volume (Grand View Research, 2014).

Among all the possible products and value streams obtained from biomass in the biorefineries, the chemical market (both commodity and fine chemicals) is expected to grow at a rate almost double to that of biofuels, since chemicals are on average priced 15 times higher than energy (Deloitte, 2014), which will entail that by 2025 at least a 45% share of chemicals will be accounted by biorenewable chemicals in the USA (Bardhan et al., 2015). In Europe, biobased chemicals account at present time for 5.5% of total turnover for chemicals produced in the EU, and they are expected to grow up by over 5% per year, until reaching a total proceeding of sales of about $44 billion in 2020 (Schneider et al., 2016).

Additionally, compared to the production of first‐generation biofuels, the production of more bio‐based materials will not have a price enhancing effect on food products (van Haveren et al., 2008) since it would be based on the utilisation of the carbohydrate fraction of lignocellulosic biomass (i.e., cellulose and hemicellulose) and inedible oil seed crops or algal oil as feedstock. In the report edited by Deloitte, the authors estimated that replacing all petrochemicals would require just 5% of agricultural biomass production and global arable land, which is about 60 times less than what would be required to replace all fossil energy (Deloitte, 2014). Straathof (2014) reported in his extensive review about the biochemical formation of commodity chemicals from biomass that 21 of the compounds cited are already commercially produced (including carboxylic acids, alcohols and amino acids), and at least 9 others have been tested at pilot scale. Frost & Sullivan (2011) calculated that the global market for fermentation derived fine chemicals was $16 billion in 2009.

However, as with all the main human inventions, modern biotechnology presents contradictions and confronts the ethic principles of our societies. It is at the same time a tool to face the main human challenges (energy needs, environment conservation, human health, food supplying, etc.), but it also represents high risks to the environment and to human health if it is not properly used. Thus, even if the use of genetically modified microorganisms (GMM) has offered advantages over traditional methods of improving chemical selectivity and the supply of desired bioproducts thus reducing production cost (Bullis, 2013), their implementation has been controversial among the general public, especially when these microorganisms contain genes introduced from other species. Taking into account that newly isolated strains of microorganisms and GMMs can be patented, pressing questions arise regarding whether these organisms have any place in our ethical considerations and how they should be treated (Cockell, 2011).

Microbial sensing, microbial nanocontrol, smart fermentations, smart enzymatic systems, and the bioinformatics can be included amongst the main new developments which will revolute the biotechnology itself. The discovery in the 1970s of sophisticated cell‐cell communication mechanisms (quorum sensing), became evident that microbial populations are synchronized at a certain cell density, by means of diverse signalling molecules that are synthesized and secreted by the microbes themselves (Bassler and Losick, 2006). Thus, the deep knowledge of the quorum sensing regulation on microbial metabolism and the control of microbial sensing will allow the complete redesign of all bioprocesses in terms of microbial signalization. We will be able to control better the bioprocesses (shortening residence times, controlling contamination, increasing production yields), to change the way to fight against microbial illnesses with new molecules (other than antibiotics) or antagonist bacteria, to improve life quality of livestock, to protect better the environment, etc.

As most of technological advances, several of these improvements obtained by microbial sensing appear so far or impossible to develop with time. But the biotechnological revolution is highly associated to the technological advances of other science branches, such as materials science, photonics, electronics, microscopy, and others. The development of new powerful and high‐sensitive analytic equipment is essential to identify microbial signals and to construct mapping interactions (Moon et al., 2010).

In the near future, transformation of biomass into chemicals using enzymes or cells will be implemented with success only if the production process is more attractive than for alternative options (petrochemical route) to produce these chemicals based on their ecologic, social, and economic value. The present book tries to show a brief portrait of the state of the art of “four magic e” bioproducts (large‐scale microbial fermentation products considering economic, ethical, environmental, and engineering aspects) and how microbial sensing has a main role in their present and future production.

1.2.2 Importance of Microbial Sensing in Product Formation

However, microbial sensing is so wide that it is necessary to delimit the goal of this work. This book presents a comparison among the different control concepts for the carbon transformation by microorganisms, analysing microbial, biochemical and molecular biology control concepts. The microbial sensing concept is emphasized showing the potentiality to use it for fermentation control and predict the scaling up.

According to the combination signals’ origin‐cell sensor, the microbial sensing defined as the identification of internal and external signals by microbial sensors can be classed in five main categories (Figure 1.2), as follows:

Internal signals. The molecules to be captured by microbial sensors are produced by the same cell in its cytoplasm. These signals are employed by the cell to control the production of functional cell structures (proteins, enzymes, organelles, etc.), as well as to control the cell aging.
Signals in a homogenous microbial community. They are produced by cells of the same species in a homogenous microbial community to control the interactions among them, for example the quorum sensing to conglomerate and begin the formation of homogenous biofilm.
Signals in a heterogeneous microbial community. They are produced by the cells of the different species present in a heterogeneous microbial community to develop synergistic or antagonistic interactions among them. For example, production of toxic molecules to inhibit the growth of competitive species.
Signals produced by the effect of environmental factors. They are caused by the effect of extracellular environmental factors such as light, humidity, ionic strength, pH or temperature.
Signals in host bodies. They are produced by both cells and infected bodies. The interactions among them can be both synergistic (e.g., probiotic microorganisms in human or animal gut) or antagonistic (e.g., pathogen infections).

Illustration of microbial sensing classification. Internal signalling (center) is interconnected to signalling in homogenous and heterogeneous communities and host bodies and signalling by environment factors. — **Figure 1.2** Microbial sensing classification according to signal origin.

The effect of environmental factors is the most known signalling mechanism of microbial sensing since their role has been clearly defined for several bioprocesses, such as alcoholic fermentations. Besides, the major efforts undertaken regarding the understanding of infections by pathogenic agents and host health and homeostasis, has contributed to gain appropriate and reliable information about the signals produced in host bodies (5^th mechanism) (Kendall and Sperandio, 2016).

The remaining categories (1‐3) became important at the end of last century, and it is precisely these categories which represent the state‐of‐the‐art in this field. However, empiric and scientific data related to the first three cases is scarce, and there are still many gaps and uncertainties in the relevant scientific knowledge about signalling processing. In addition, the experimentation with animal or human models is a very sensitive subject constrained by ethic rules which must be respected, limiting the number and the quality of the scientific research. Therefore, even if all kind of microbial sensing is now studied around the world, there is a lack of updated reviews showing the most important advances done during the last 5‐10 years.

1.3 Conclusion

The present book documents and critiques those aspects related to microbial production and performance, including the type of carbon source, cellular and biochemical control over the microbial products, etc. from the perspectives of molecular biology and biochemistry. Together with these aspects, the ways to quantitatively and qualitatively control the microbial products as well as approaches to scale‐up and optimize these processes along with specific future market perspectives and policy initiatives are thoroughly reviewed in this book. Accordingly, it will be of particular interest for those researchers working in the field of microbial biotechnology but it will also cover those areas related to molecular biology, biochemistry and materials science, among others.

Acknowledgments

The authors wish to acknowledge the financial support received from the State Agency for Research (AEI) of the Spanish Government and the European Regional Development Fund (FEDER) (Project CTM2016‐77212‐P). We thank the Basque Government (Department of Education, Language Policy and Culture) and the Fonds de recherche du Québec – Nature et technologies (FRQNT) for the postdoctoral grant to Dr. Larrañaga and the postdoctoral scholarship of short duration to Dr. Gallastegui, respectively. We thank also the Discovery‐NSERC program for the funds to finance the postdoctoral internship of Dr. Pham.

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