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0INTERNATIONAL SCIENTIFIC AND PRACTICAL CONFERENCE "STATUS AND DEVELOPMENT PROSPECTS OF FUNDAMENTAL AND APPLIED MICROBIOLOGY: THE VIEWPOINT OF YOUNG SCIENTISTS" _25-26 SEPTEMBER, 2024_
OVERVIEW OF MICROBIAL BIOSYNTHESIS FOCUSING ON
VITAL NATURAL PRODUCTS
1Abdul Rahman Khan, 2Shahzadi Bano, 3Jamal Akhtar Ansari, 4Farogh Ahsan
U'3'4Department of Chemistry, Integral University, Dasauli, Kursi Road, Lucknow (India)-
226026
https://doi.org/10.5281/zenodo.13828156
Introduction
Microorganisms have existed on Earth for about 3.5 to 4 billion years, constantly evolving and adapting to new environments, and they can be found everywhere. Their presence has played a crucial role in the development of new ecosystems, some of which have paved the way for the evolution of more complex life forms [1]. Microorganisms can communicate with each other, and some produce signals that help form metabolically diverse communities. Without their metabolism and communication, the recycling of essential nutrients on Earth would cease. When faced with harsh conditions, microorganisms adapt and produce secondary metabolites that are vital to their life cycles. These secondary metabolites also have potential applications in medicine, industry, and disease treatment and prevention [2]. Biosynthesis is the process by which living microorganisms modify or combine simple molecules to create larger macromolecules [3]. Natural products, which are unique organic compounds produced by microorganisms as end products of secondary metabolism, have applications in alternative medicine, cosmetics, dietary supplements, and drug discovery [4]. This article explores various biosynthetic processes and secondary metabolites produced by microorganisms, as well as the potential importance of natural products in pharmaceutical, medicinal, and industrial biotechnology.
Brief history
Microorganisms are tiny communities that can only be seen with a microscope. These organisms, whether they are natural isolates, lab-selected mutants, or genetically engineered strains, are used in the production of vitamins, amino acids, enzymes, and various fermented products like sour cream, yogurt, buttermilk, pickles, sauerkraut, bread, and alcoholic beverages. Applied microbiology, particularly in biotechnology, plays a significant role in utilizing these microorganisms. They are also essential in the production of pharmaceuticals that cannot be manufactured through other means, including human hormones like insulin, antiviral substances such as interferon, various blood-clotting factors, clot-dissolving enzymes, and several vaccines [5].
The term "microbiology" was originally linked to the study of the causes of infectious diseases. However, as the field developed, it led to significant practical applications of microorganisms across various scientific disciplines. In the mid-1600s, shortly after the invention of the microscope, English scientist Robert Hooke made important observations about microorgani sms [6]. It wasn't until the 1670s and the following decades that Dutch merchant Anton van Leeuwenhoek introduced the microscopic world to other scientists. He was one of the first to provide detailed and accurate descriptions of protozoa, fungi, and bacteria, which were then referred to as "Animalcules." After van Leeuwenhoek's death, the study of microbiology progressed slowly due to the rarity of microscopes and limited interest in microorganisms [6]. It wasn't until the mid to late 1800s that Louis Pasteur discovered the cause of souring in wine and dairy products, thereby confirming the crucial role of microorganisms in human life [6].
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Biocatalysis, a key component of biotechnology, broadly refers to the use of enzymes (biocatalysts) to facilitate or accelerate specific chemical reactions. Microbial catalysts have long been employed in the food industry and are now expanding into various fields, including industrial chemistry [7]. Biocatalysis utilizes whole microbial cells, cell extracts, purified enzymes, immobilized cells, or immobilized enzymes. Recent advancements in large-scale genome sequencing, directed evolution, protein expression, metabolic engineering, high-throughput screening, and structural biology have driven rapid progress in biocatalysis [8]. The global market for industrial enzymes reached $3.3 billion in 2010 and grew to approximately $4.4 billion by 2015 [9]. Among these, technical enzymes are commonly used in bulk applications within the detergent, textile, pulp and paper, and biofuels industries. The leather and bioethanol sectors, in particular, generate the highest sales. Revenues from technical enzymes were nearly $1.2 billion in 2011, $1.5 billion in 2015, and are projected to reach $1.27 billion in 2021 [9], with the biofuels (bioethanol) market expected to lead in sales.
Biocatalysts are complex protein molecules produced within living cells. They possess catalytic properties, enabling specific chemical transformations that are crucial for bioprocesses in the food, feed, agricultural, chemical, and pharmaceutical industries. Enzymes, as true catalysts, are increasingly replacing chemical processes in various industries. However, the purity of biocatalysts is especially important in food manufacturing and pharmaceuticals, as by-products can be harmful or impact flavor. The precise chemical transformations performed by microbial enzymes have made them highly desirable in industries for several reasons: (1) less specific chemical processes often generate unwanted by-products; (2) enzymatic reactions occur at a much higher rate without consuming the enzyme; (3) biocatalysts have become the preferred choice for industrial bioprocesses seeking cost-effective, reliable, and scalable methods with minimal waste; (4) enzymes offer advantages such as controllability and the ability to operate under mild
Figure 1: Possible plant microorganism interaction
Biocatalyst
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conditions, like temperatures of 20-40°C and pH ranges of 5-8; (5) biocatalysts are fully biodegradable, and their yields can be predicted; and (6) many industrial processes are designed for elevated temperatures, where chemical reactions are faster and issues with viscosity and contamination are minimized [10]. Biocatalysts are widely accepted in the food, pharmaceutical, and fine chemicals industries, leading to the development of innovative biocatalytic reactions that are now mature enough for commercial exploitation [9] (Table 1).
Table 1: Plant-derived compounds interaction with microorganisms and how these interactions can impact drug metabolism and effectiveness
Plant Plant Microorganism Impact on Drug Clinical
Compound Source Interaction Interaction Significance
Quinones Ginkgo Bacteria: Some May alter the Potential
biloba, bacteria can bioavailability of modification of
Rhubarb metabolize quinones (e.g., Pseudomonas) quinone-based drugs. therapeutic efficacy.
Flavonoids Citrus Fungi/Bacteria: Can May influence drug Can enhance or
fruits, affect microbial metabolism by inhibit the effects
onions, tea enzymes (e.g., Candida, E. coli) affecting liver enzymes. of certain drugs.
Glycosides Bitter Bacteria: Gut May affect the Changes in drug
almonds, microbiota can activation or efficacy or toxicity.
cassava hydrolyze glycosides (e.g., Lactobacillus) inactivation of glycoside-based drugs.
Alkaloids Coffee, Bacteria/Fungi: Can May alter the Impact on the
tobacco, be metabolized by pharmacokinetics and effectiveness and
opium gut microbiota (e.g., dynamics of alkaloid safety of alkaloid
p°ppy Enterococcus) drugs. medications.
Terpenes Mint, Bacteria/Fungi: Potential interaction Can lead to
ginger, Some microbes with drugs by altering synergistic or
cannabis metabolize terpenes (e.g., Aspergillus) metabolism. antagonistic effects with medications.
Saponins Ginseng, Bacteria: Gut May influence the Modulation of
soybeans bacteria can absorption and therapeutic
hydrolyze saponins effectiveness of outcomes and
(e.g., Clostridium) saponin-based drugs. potential side effects.
Phenolics Apples, Bacteria: Can Potential interference May affect the
berries, tea impact microbial with drug metabolism absorption and
enzyme activity (e.g., and efficacy. action of certain
Lactobacillus) drugs.
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Coumarins Sweet clover, celery Bacteria/Fungi: Can be metabolized by gut microbiota (e.g., Bacillus) Potential alteration of drug metabolism and interactions. Significant for drugs with narrow therapeutic windows.
Tannins Tea, grapes, oak bark Bacteria: Can affect the gut microbiome (e.g., Bacteroides) May influence drug absorption and efficacy. Can impact the effectiveness of medications, particularly those requiring optimal absorption.
Biosynthesis
Biosynthesis is the process by which living microorganisms create organic compounds. During this process, simple compounds are modified, transformed into other compounds, or combined to form macromolecules. Biosynthesis involves numerous metabolic pathways, some confined to a single cellular organelle, while others involve enzymes located in multiple organelles. This process requires a series of chemical reactions, with precursor compounds, catalytic enzymes, cofactors, and chemical energy playing essential roles [11]. Bioactive microbial metabolites are notable for their interaction with the environment and their unique chemical structures [9]. Natural products, including microbial metabolites, can be used in three primary ways: (1) applied directly in medicine, agriculture, or other fields; (2) used as starting materials for chemical or microbiological modifications (derivatization); and (3) as lead compounds for chemical synthesis of new analogs or templates in rational drug design studies [2]. Research into the biosynthetic pathways of bacteria and fungi has shown that many protein factors are involved in biosynthesis. The regulation of these pathways, which includes macromolecular interactions and the control of specific enzymes and catalytic reactions, is well-documented in bacteria and fungi. Biological systems generate chemical diversity, with some biosynthetic pathways producing a single metabolite, while others are more flexible, generating a variety of compounds [12]. Primary biosynthetic product
Primary metabolites are produced during the exponential growth phase as typical end products of primary metabolism. In this process, the production curve aligns with the growth curve, with metabolites like vitamins, amino acids, and nucleosides being generated to support cell growth [13]. Examples of primary metabolites are provided below.
Vitamin
Microorganisms synthesize vitamins and other growth-stimulating compounds using the chemical constituents of the culture medium. These compounds are produced in excess of the microorganisms' needs, accumulate in the cultures, and are subsequently recovered. Microorganisms are commercially utilized to produce vitamins on a large scale under various cultural conditions [14]. Examples of vitamins produced through microbial processes include carotene, a precursor of Vitamin A from Blakeslea trispora; riboflavin from Ashbya gossypii; L-sorbose, used in Vitamin C synthesis, from Gluconobacter oxidans; and Vitamin B12 from Bacillus coagulans, Bacillus megaterium, Pseudomonas denitrificans, and Streptomyces olivaceus [15].
Amino acid
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Microbial fermentation of substrates such as glucose, acetate, and sucrose by different microorganisms can produce amino acids like D- and L-alanine, L-glutamic acid, L-leucine, L-lysine, and L-threonine. For example, Microbacterium ammoniaphilum ferments glucose to produce D- and L-alanine, Micrococcus glutamicus generates L-glutamic acid from glucose, and Brevibacterium lactofermentum yields L-leucine. Brevibacterium flavum ferments acetate to produce L-lysine, while Escherichia coli K12 converts glucose into L-threonine. Additionally, primary metabolites like L-glutamate and L-lysine, which are often used as dietary supplements, are obtained through the mass production of Corynebacterium glutamicum [9].
Organic acids
The metabolism of carbohydrates leads to the production and accumulation of organic acids. These purified organic acids are manufactured on a large scale and sold either as pure chemicals or as their respective salts. Organic acids can be either the final products of the Embden-Meyerhof-Parnas (EMP) pathway, such as lactic acid and propionic acid, or products of the incomplete oxidation of sugars, like citric acid, itaconic acid, and gluconic acid. Calcium lactate was first produced on a large scale via bacterial fermentation in 1981. Since then, species of Penicillium and Aspergillus have been employed in organic acid production. Organic acids are utilized across various industries and research fields. For instance, acetic acid is used in the food industry and for research purposes, fumaric acid is employed in resin production, and the calcium, iron, and potassium salts of gluconic acid are used in medicines and cleaning products. Lactic acid finds applications in the food industry (e.g., for fruit extracts, syrups, and pickles), as a dye mordant, in tanning, in skin decalcification, and in plastics, as well as in medicine in the form of calcium and iron lactates. Citric acid is used in the food industry (e.g., for fruit drinks, confectioneries, jams, jellies, preserved fruits, and candies), in pharmacy (e.g., for blood transfusions and effervescent products), in cosmetics (e.g., in astringent lotions, shampoos, and hair setting fluids), and in various industries (e.g., electroplating, leather tanning, pipe cleaning, and reactivation of old oil wells) [16].
Secondary biosynthetic product
Biological structures have long inspired solutions to technical challenges in fields like architecture, mechanical engineering, and materials science. Nature has created materials and biopolymers with exceptional properties. A natural product is something that occurs naturally and is not artificially made, often implying purity. Metabolic pathways in living systems fall into two main categories: those that produce a few specific chemicals, and those that generate a wide range of metabolites. The latter, known as diversity-generating pathways, are responsible for many small molecules in living systems. These pathways do not produce a single end product; instead, they involve enzymes with broad substrate specificities that handle various compounds [17].
Biopolymer
Biopolymers are large molecules made from monomeric units, bonded covalently, and produced by living organisms, making them biodegradable. These polymers can be derived from various biological sources like microorganisms, plants, or trees. Known as green polymers, biopolymers are often made partially or entirely from renewable natural resources. Unlike synthetic polymers, which have simpler and more random structures, biopolymers are complex molecular assemblies that adopt specific 3-D shapes, making them active in biological systems. Their structure, biocompatibility, and biodegradability are crucial to their function. Microorganisms produce various biopolymers, such as polysaccharides, polyesters, and
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polyamides, with physical properties dependent on their composition and molecular weight. Bacteria, for example, produce different polysaccharides, which can be classified by their biological functions: intracellular storage (e.g., glycogen), capsular (linked to the cell surface), and extracellular polysaccharides (e.g., xanthan, alginate, cellulose). These biopolymers, synthesized through various biosynthetic pathways, are encoded by specific gene clusters in the producing organisms. Due to their superior material properties, biocompatibility, and biodegradability, biopolymers have numerous medical and industrial applications, where they can enhance the performance of other biologically active molecules or be modified for various uses [18]. Biopolymers are increasingly used and commercially available in the food industry as coatings, food packaging materials, and encapsulation matrices for functional foods. Their growing popularity stems from their ability to incorporate various functional ingredients, which not only extend product shelf life but also reduce the carbon footprint associated with food packaging. Materials derived from biomass, such as proteins, polysaccharides like chitosan, and lipids like waxes, are also effective as gas and aroma barriers [18]. Biopolymers are used in encapsulation technology to protect sensitive substances from adverse environmental conditions. Microencapsulation, a process of enclosing solids, liquids, or gases in small capsules, releases their contents under specific conditions and is of particular interest to the pharmaceutical industry. A key advantage of biopolymer coatings is their ability to carry natural or chemical active ingredients, such as antioxidants, antimicrobial agents, enzymes, or functional components like probiotics, minerals, and vitamins. These ingredients can be consumed with the food, enhancing safety, nutrition, and sensory qualities. Additionally, edible films can serve as flavor or aroma carriers while preventing aroma loss [19].
Hydrophilic polymers typically suffer from poor moisture resistance, leading to water vapor transmission through packaging, which can compromise food quality. The hydrophilic nature of certain biopolymers limits their use in premium products because moisture absorption can cause plasticization, weakening their barrier properties. This deterioration results in shorter shelf lives, higher costs, and increased waste. Chitosan has emerged as a promising antimicrobial packaging material, effectively preserving food against a range of microorganisms. Incorporating antimicrobial compounds into edible films or coatings is a novel approach to enhancing the safety and shelf life of ready-to-eat foods. Lysozyme, a naturally occurring enzyme, is commonly used as an antimicrobial agent in packaging materials. Additionally, biopolymers like amylose, when combined with plasticizers, show great potential for forming thin films suitable for various food and packaging applications [20] (Table 2).
Table 2: Highlighting the relationship between plant metabolites and microorganisms, illustrating their interactions and potential applications.
Type of Metabolite Plant Examples Microorganism Interaction Function/Usage
Primary Metabolites
Carbohydrates Corn, wheat, potatoes Bacteria: Assist in breakdown and fermentation (e.g., Lactobacillus in fermentation) Source of energy and carbon for growth, used in food and fermentation processes.
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Amino Acids Soybean, Fungi: Mycorrhizal fungi help Building blocks for
spinach, in nutrient uptake, some fungi proteins, essential for
beans produce amino acids (e.g., Aspergillus) growth and metabolism.
Proteins Peas, beans, Bacteria: Decompose plant Essential for growth and
lentils proteins (e.g., Bacillus) cellular functions.
Lipids Olive, Yeasts: Can convert plant oils Energy storage, cell
sunflower, into biofuels (e.g., membrane structure.
soy Saccharomyces cerevisiae)
Secondary Metabolites
Alkaloids Coffee, Fungi: Can produce alkaloids Defense compounds, used
tobacco, in symbiotic relationships (e.g., in pharmaceuticals (e.g.,
potatoes Claviceps purpurea) caffeine, nicotine).
Terpenes Citrus fruits, Bacteria: Some bacteria can Aroma and flavor
mint, produce terpenes (e.g., compounds, used in
lavender Streptomyces) perfumes and essential oils.
Flavonoids Apples, Fungi: Can metabolize Antioxidants, UV
onions, flavonoids (e.g., Aspergillus) protection, used in food
grapes colorants and dietary supplements.
Phenolics Apples, Bacteria: Can degrade Antioxidants, contribute to
berries, tea phenolics (e.g., Lactobacillus) color and flavor, used in medicinal applications.
Glycosides Bitter Bacteria: Can hydrolyze Defense compounds, used
almonds, glycosides (e.g., Clostridium) in pharmaceuticals (e.g.,
cassava digoxin).
Saponins Ginseng, Fungi: Can produce saponins Have antimicrobial and
soybeans in symbiotic relationships (e.g., Aspergillus) immune-modulating effects, used in pharmaceuticals.
Antimicrobial Natural product
Microorganisms like bacteria, fungi, and mold produce various antimicrobial secondary metabolites that can inhibit other microorganisms. These metabolites are typically synthesized after the active growth phase to outcompete other organisms in the same ecological niche. For example, secondary metabolites from bacteria and fungi, such as penicillins and tetracyclines, are widely used as antibiotics. Antimicrobial agents encompass all substances that act against bacteria, viruses, and fungi. Filamentous microorganisms like fungi and actinomycetes are the primary sources of antibiotic secondary metabolites.
Bacteriocins, protein-based antibacterial compounds, are commonly produced by lactic acid bacteria and other Gram-negative and Gram-positive bacteria. These compounds, including nisin and pediocin, are valuable as food preservatives because they target bacterial membranes. Actinomycetes, which produce over 10,000 antimicrobial agents, have diverse biological activities, including antibacterial, antifungal, antiviral, and anticancer properties. The discovery of
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antibiotics from actinomycetes marked a significant advancement in medicine, with 75% of broad-spectrum antibacterials originating from these organisms. Streptomyces species alone are responsible for producing 74% of all actinomycetales-derived antibiotics, with important classes including P-lactams, aminoglycosides, and macrolides [21]. Bacterial Survival Strategies
Microorganisms can be either beneficial or harmful, and understanding the stress factors they encounter and their resistance mechanisms is crucial for biotechnology. Under stress, bacteria produce specific proteins that help them survive and adapt to harsh conditions, acting as molecular markers of stress. These stress-adapted bacteria can cause food spoilage and pose significant risks to public health, especially in developing countries. Foodborne pathogens can survive and thrive in various environments, forming biofilms on surfaces in food processing plants and medical devices. Their survival and growth depend on factors like pH, temperature, and the presence of antimicrobials. Some bacteria can produce spores, making them more resistant to adverse conditions.
For a foodborne pathogen to cause infection, it must first survive food processing treatments and then withstand the human body's defenses, such as gastric acid and bile salts. Bacteria achieve this by sensing environmental changes and adjusting their gene expression and protein activity accordingly. Understanding these survival mechanisms is a key scientific challenge. In the context of food safety, there's a growing demand for foods that promote health and prevent disease, leading to the emergence of nutrigenomics, which studies how food components can influence gene expression to reduce disease risk. The future of food science lies in developing healthy, functional foods that address consumer demands and contribute to better public health. This requires a multidisciplinary approach involving biological science, food science, engineering, marketing, and regulation [22]. Conclusion
Concerns about safe, healthy food have driven research into replacing chemical compounds with green biomaterials. Studies are exploring methods for producing renewable monomers and polymers, focusing on their benefits and drawbacks. There is a growing need for green substitutes in food, medicine, and pharmaceuticals. Microbial synthesis, particularly biosynthesis, is gaining attention due to its efficiency and ability to produce essential primary and secondary metabolites. Green chemistry approaches using microorganisms offer advantages like ease of scaling up, economic viability, and health safety. Natural products from microorganisms are valued for their chemical stability and biocompatibility in various fields, including food, pharmaceuticals, and agriculture. Microorganisms have long been used for producing biochemicals such as alcohols and antibiotics, and their role is expanding with increased resources dedicated to developing green biopolymers, biomaterials, biosurfactants, and other applications.
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