Recent Advances in the Application of Marine Natural Products as Antimicrobial Agents

The need for the identification of novel antimicrobial agents is greater than ever due to the emergence of multidrug resistance (MDR) among clinically important pathogens which pose serious threats to public health worldwide. Unfortunately, the pace of discovery and development of new antimicrobial agents to treat MDR infection has significantly slowed down. Identifying new targets and chemical classes is not easy, and reinvestigating old strategies by testing new compounds on known targets and expecting novel outcomes, seems not only a failure but a border on insanity. The development of new antimicrobial agents, chiefly those with novel mechanism(s) of action, remains essential, but this alone does not guarantee success. It is important to explore diverse information from multiple strategies, including multi-omics, bioinformatics, system biology and other non-conventional approaches. In this chapter, we give a brief background on the importance of antimicrobial drug discovery, detail several discovery platforms from target-based discovery to the current innovative strategy being evaluated, and list the challenges alongside each platform.

The discovery of drugs for human ailments has been greatly attributed to nature ever since the existence of mankind. Continuous isolation of metabolites from terrestrial resources leads to a bargaining effect on the synthesis of novel compounds. Remarkably, marine biotope, one of nature’s resources, accommodates approximately 75% of the global surface. To acclimatize in a marine environment characterized by unique circumstances that diverge from the individuals present in other habitation, marine organisms occasionally accumulate structurally distinctive bioactive secondary metabolites that are deficient in terrestrial organisms. Marine metabolites are currently employed as the key components in pharmacological research and drug discovery, acting as drugs and active lead molecules towards the development of novel antimicrobials. Numerous marine metabolites that are derived from macro and microorganisms have attained the level of clinical assessment. Hence, marine environments are considered tools for discovering new antimicrobial agents as they comprise a vast untapped reservoir of metabolite diversity.

The marine environment comprised huge biological diversity and remained the least explored location for prospecting novel antimicrobial agents. Marine bacteria, in specific, are considered an essential source of therapeutically valuable biologically active secondary metabolites. As bacteria are ubiquitous, they evolve with a certain unique mechanism to thrive under stressful conditions like competitive habitats, much-varied temperatures, light, pH and pressure. In these harsh environments, surprisingly, bacteria in these regions produce many natural bioactive compounds with unique molecular scaffolds and structural complexity. This untapped biological resource may become a source for the cure of several crises facing the world in the 21st century, such as the emergence of multi and pan-drug-resistant bacterial and fungal pathogens and pandemic and epidemic outbreaks of viral infections. This chapter discusses the role of natural secondary metabolites from marine-derived bacteria as a tool in the fight against emerging and re-emerging infectious diseases. 

Antimicrobial property has been the reason for investigation in several plants and microorganisms. The health issues and environmental hazards defined by the extensive use of chemical antimicrobials have become a buried fact due to the emergence of bio-based antimicrobial agents. Considering the impact of chemical antimicrobials on the environment, many natural antimicrobial agents have been formulated and recommended for application in food systems. Several food-borne outbreaks are associated with the intake of marine foods and are highly linked with harmful microbial pathogens. Marine bacterial pathogens have been extensively reported for several outbreaks in the last few decades. Vibriosis is the most devastating disease faced by marine organisms. The associated pathogens have also been channelized to humans through seafood consumption. There also exist some deadly bacterial pathogens in marine environments, which are responsible for huge economic losses in seafood processing sectors. It is high time to mitigate this bacterial jeopardy. The extended anthropogenic activity on the coastal lines has also increased the virulence of these bacterial pathogens by inducing multidrug resistance. Based on several reports in the pre and post-antibiotic era, phage therapy is revitalised to overcome the limitations encountered in antibiotic therapy. Marine bacteriophages are documented as abundantly available viruses in the marine environment. Their ubiquitous and inevitable nature can be utilized to engage them as natural antimicrobial agents from the marine environment and its allied sources. This chapter summarized the feasibility of employing bacterial viruses from the marine environment as natural antimicrobial agents with proper evidence from the past

Marine cyanobacteria are oxygenic, gram-negative nitrogen-fixing photosynthetic prokaryotes in different environments. It is a universal organism present in aquatic and terrestrial and also extensively scattered in extreme habitats such as hot springs, deserts and glacial environments. Growing concerns over disease outbreaks and other environmental concerns require alternative ways that are economically viable, sustainable, as well as feasible. Recently, cyanobacteria have achieved much consideration because of their potential relevance in various fields, including aquaculture, wastewater treatment, food, fodder, and the production of secondary metabolites, including polysaccharides, vitamins, toxins, enzymes and pharmaceuticals; they also secrete important novel bioactive antimicrobials including antibacterial, antifungal and anti-viral compounds. The emergence of antimicrobial resistance among pathogenic microbes against common antibiotics imposed the search for new antimicrobial agents from natural sources. Various features of cyanobacteria, including their ability to produce novel antimicrobials, make them suitable candidates for their exploitation as a natural source. Hence, this chapter presents an overview of marine cyanobacterial features, antimicrobials isolated from marine cyanobacteria, as well as the mode of action. Among the known cyanobacterial bioactive compounds, many are pharmacologically important and hold immense potential for drug development at the clinical level

Antimicrobial compounds are groups consistent with the microorganisms that they could potentially act against bacteria or fungi. It is expected to kill microorganisms or inhibit their growth and activity. As the case of antimicrobial resistance increases, nature has been generous in providing compounds with the potential to treat various ailments and infectious diseases. Bacteria, fungi and plants are known to own a good list of antibacterial molecules. Although research has been carried out to reveal the antimicrobial potential of natural products, the significance of vast terrestrial and marine Animalia has gained momentum. Though the naturally available antimicrobial agents obtained from plants, animals and microbial sources are considered safe in comparison with synthetic molecules, the outbreak of pathogens needs exploration over and above the reported ones. As the synthetic antimicrobials soon become immune to pathogens, it makes emphasis on antimicrobials from novel origins that have a long duration of effectiveness. The marine environment houses a wide and taxonomically diverse species of algae, mollusks, sponges, corals and tunicates. These organisms have adapted to survive the infectious environment by producing pharmacologically active compounds of phlorotannins, fatty acids, polysaccharides, peptides, and terpenes that help in battling bacterial annexation. As marine algae provide considerable opportunities in antimicrobials, the optimization in the methodologies leading to extraction and purification plays a greater role in capturing the antimicrobial activity of the bioactive molecules. Though an outsized number of potential antimicrobial compounds from marine algae have been identified and isolated, the majority of those compounds are yet to be categorized and commercialized. Recent research in algae focused on “omics” where metagenomics, metatranscriptomics and metaproteomics are done to understand better pathway leading to the synthesis of various functional molecules.

Mangroves are a promising source of antimicrobials owing to the bioavailability of genes, plant metabolites and biological diversity. Mangroves are known for their many biological properties, such as antibacterial, antifungal, antiviral and anti-cancer activities etc. Besides mangroves, the microbes associated with mangroves are called endophytes, which are proven effective antimicrobials and are also well-known for their many other pharmacological properties. Mangrove extracts coated with nanoparticles exhibit better antimicrobial activity due to their easy absorption and distribution properties. The antimicrobial activity of mangroves is due to the presence of abundant phenolic and flavonoid compounds, especially tannins, and to the antioxidant property of the bioactive substances present in the mangroves. Thus, mangroves have a great bioprospecting potential for developing the most potent antimicrobials to treat pathogenic bacteria, viruses and fungi. This chapter deals with the antibacterial, anti-viral, anti-mycotic, anti-virulence and anti-biofilm properties of mangrove extracts and mangrove endophytes against various pathogenic and multidrug-resistant microbes. In addition, patenting of natural compounds from mangroves and their endophytes, as well as metabolomics and proteomics, are also discussed in this chapter.

In recent decades, both the growing global resistance to existing antibiotics and the shortage of new groups of compounds identified have become a public health concern. In order to solve it, researchers are now focusing their attention on unconventional sources, including microbes from harsh environments. In this context, the aim of this study was to determine whether marine sponges have the ability to inhibit the growth of microorganisms that are terrestrial in origin and pathogenic to humans. The majority of these chemicals have so far been found in marine invertebrates, primarily sponges. Marine sponges are a rich source of structurally specific natural substances, some exhibiting a diverse variety of biological activities. Also, excellent sponge drug candidates are often overlooked because the sponges are either rare or difficult to obtain, or both. Sponges have piqued the interest of scientists who want to learn more about the associated microbial community and the useful metabolites they produce, which can be used in pharmaceutical and biotechnological applications. The ecological importance of mutualistic relationships between marine sponges and their related microbes cannot be overstated. These bioactive compounds from microbes protect their hosts from a variety of microbial diseases. These results indicate that the antimicrobial properties of marine sponge extracts may be used as a complementary or replacement method for treating microbial infections.

The emergence of multidrug-resistant (MDR) among pathogenic organism puts human and animal lives at stake. As a result of that, researchers in the scientific community tirelessly made efforts to search for novel antimicrobial agents to combat the pathogenesis of multidrug-resistant pathogens. Marine environment represents a vast diversity of lives that interact with each other and thus have to protect themselves against infectious pathogens. Hence, they present an armamentarium of diversified biomolecules with different mechanisms of action, which aids the survival of the host in the very same environment. Among the natural biomolecules, antimicrobial peptides (AMPs) gain more attention owing to their potential action as antimicrobial agents against several infectious diseases. With the emergence of MDR pathogens, AMPs are currently deemed to be the next generation of antibiotics. The quest of these AMPs was initially focused on the terrestrial environment for years. By knowing the presence of the least explored and diverse organism, the focus on the quest of AMPs is now heading toward the marine ecosystem. The current chapter focuses on the benefits, confronts and chances of using AMPs against MDR pathogens, and also emphasizes the need and importance of designing a focused development tactic to support the advancement and potential application of AMPs in medicine.

This chapter centers on the novel marine metabolites from marine organisms, especially peptides and other therapeutic agents. The major component of the innate immune defense system, also regarded as the first line of defense, is the antimicrobial peptide, which not only boosts resistance but also displays promising curative properties. The isolation, potential antimicrobial activity, various properties, mechanism and sources of diversified antimicrobial peptides distributed in various phyla of marine invertebrates, along with their potential role in the therapeutic arena, are explored. The most popular conotoxin peptide Zincnotide was available as a drug (Prialt®) and entered the market as a potent analgesic agent. Ethionamide (Trecator®), a nicotinamide derivative, isolated from porifera possessing antibacterial activity, is used to treat tuberculosis. Similarly, a number of peptides have been reported for exhibiting antimicrobial activities in marine organisms. Hence, the present chapter is mainly focusing on the list of marine invertebrates’ antimicrobial peptides and their therapeutic applications. 

Increasing threats due to microbial infections during disease outbreaks resulted in excessive usage of antibiotics. Even during viral disease outbreaks, antibacterial agents are widely prescribed to control bacterial co-infections as a precautionary measure. Moreover, inappropriate use of antibiotics steered towards the development of resistance against a diverse group of antibiotics. Dispersion of multidrug-resistant (MDR) pathogens in the environment is one of the reasons for the development of multi-drug resistance among opportunistic and commensal organisms. This poses a major risk to the healthcare sector. Excessive usage of antibiotics not only results in antibiotic resistance but also in multiple healths associated diseases in humans, such as ulcers, abdominal cramps and discomfort, and anaphylactic shock. Hence, a safe, target-oriented drug with or without minimum side effects is demanded to control multi-drug resistant (MDR) pathogens. The marine environment hosts the habituation of several plants, animals, and microorganisms. It also harbors novel, potent therapeutic agents against emerging pathogens. Recent research reports state that biosurfactants from marine bacteria, fungi, algae, animals, and plants possess targeted activity against human pathogens. These biosurfactants restrict the growth of microbial pathogens by several mechanisms. Biofilm formation is the major mechanism adopted by many MDR strains to overcome antibiotic treatment. Biosurfactants are reported to prevent even compact biofilms by preventing the adhesion of pathogenic bacteria to the host system or clinical devices. Also, they inhibit cell-to-cell signalling and down-regulate the genes coding for biofilm formation, thereby ensuring the complete removal of MDR pathogens. Novel biosurfactants from marine sources render a wide opportunity in drug selection to combat multi-drug resistant organisms.

Marine environment upholds vast biodiversity, which also acts as a treasurer of a huge variety of bioactive molecules. Bioactive components of marine origin range from peptides, lipids, fatty acids, proteins, minerals, phenolic compounds, vitamins, terpenoids, polyketides, polysaccharides etc. Marine-derived peptides have been explored to a larger extent for their biological applications. In recent years, polysaccharides, one of the essential macromolecules in all forms of living, have been gaining attention for their relevance in biological applications. Among the polysaccharides derived from various living forms, marine-derived polysaccharides are effective in terms of their biological activities owing to their structural diversity, composition, availability etc. Marine polysaccharides exhibit a broad spectrum of biological and pharmacological activities ranging from anti-inflammatory, antioxidant, anticancerous, antidiabetic, antioxidant, antidiabetic and immunomodulatory activities. Additionally, these bioactive polysaccharides also exert antimicrobial activities against a broad range of clinically important pathogenic organisms. Due to their excellent antimicrobial activities, marine polysaccharides, their sulfated derivatives and polysaccharide-based nanoparticles are gaining attention in biomedical applications such as wound dressing, drug delivery, tissue engineering etc.

The marine environment havens a massive number of species that are the source of a wide range of structurally diverse bioactive secondary metabolites. The importance of marine natural products (MNPs) in drug discovery has been documented extensively with their impact on the development of existing drugs. Despite the promising activity of MNPs, most of them suffer from their complex structures, instability, and poor solubility. The synthetic derivatives of natural products cover the chemical derivatization of scaffolds isolated from marine sources and are highly applicable as chemical biosynthesis and structural modifications provide new insights into the bioactivities and the dealings against specific targets that are important for exploring the indefinite chemical space. Also, engineering of the biosynthetic pathway has shown its ability to drive analogies arising from a variety of alterations, including replacement of residues, feeding with non-natural precursors, and enzyme knockout. Such arrays of synthetic compounds execute functionally distinct biological activities against various microbial pathogens, considering MNPs valuable products in the current era of drug discovery. This chapter describes the strategies and principles for the development of synthetic drugs, as divulged by several fruitful medicines that are derived from marine origin.

Worldwide, aquaculture organisms are often infected by viruses, bacteria, fungi, and parasites. These organisms are responsible for the high mortality, leading to major financial loss in this industry. Controlling microbial diseases in aquaculture is not that easy; it is much more difficult than prevention because it is a complex environment. Farmers are using different strategies to overcome this issue; however, recognizing new dietary supplements for preventing the disease is always helpful to aquaculture farmers. More recently, the bioreduction of nanoparticles using seaweed extract and its sulfated polysaccharides are fascinated because of the presence of various bioactive properties. Also, it is well-accepted that the green chemistry approach is a superior alternative to the synthesis of non-toxic nanoparticles. This chapter covers the major microbial disease in aquaculture and its management, the application of nanoparticles in aquaculture, the importance of seaweed and its sulfated polysaccharide-mediated silver nanoparticles and its role in Vibriosis and WSSV disease control in aquaculture. This chapter provides a superior understanding to the researchers for formulating novel health supplements using seaweed and its sulfated polysaccharides mediated nanoparticles to overcome bacterial and viral disease in aquaculture.

The massive increase in the world’s population has placed an undue strain on the available resources for pharmaceuticals. As a result, drug producers are constantly on the lookout for new resources that will allow them to build effective and safe pharmaceuticals to meet the growing demands of the world’s population. However, three fourth of the earth’s surface is covered by the marine environment, studies into the pharmacology of marine creatures have been limited, and much of what has been discovered is still undiscovered. The marine environment is a plethora and diversified source of novel medications to treat important diseases like cancer and malaria, among others. Marine natural products have distinct, previously unexplored diversifications as well as a diverse range of intriguing biological potentialities that are characterized by unique mechanisms of action. Recently discovered and preclinically researched marine bioactive antimicrobials are the focus of this chapter.

Marine environment has long been shown as the source of diverse organisms and niche for numerous bioactive agents. Marine natural products are of recent interest attributing to their novelty and abundant potential in the field of medicine as well as others. In spite of this recent attention, the marine environment still exists as an under-explored and untapped resource for bioactive agents, highlighting the presence of plentiful opportunities. Bioactive molecules of marine origin have been frequently reported from the microorganisms associated with marine sediments, seawater, coral and its mucus; higher-order marine organisms, mangroves, sponges, seaweeds and sea grasses, etc. Last decade has shown copious publications reporting the bioactive potentials of marine natural products such as antimicrobial, antiviral, antiparasitic, anticancer, antioxidant, anti-inflammatory and anti-infective properties. Recent studies have also opened an avenue in marine natural product research where the discovered natural products are chemically modified to attain increased bioactivity. Such modified or altered marine natural products were of great demand in pharmaceutical, food, cosmetic and chemical industries, and hence protected by product and process patents. This chapter summarizes the intellectual property rights in the form of patents protecting marine natural products with antimicrobial potentials, including antibacterial, antifungal and antibiofilm activities. This chapter also highlights the patents and applications of modified or semi-synthetic agents related to marine natural sources with antimicrobial properties.