Recent Trends and The Future of Antimicrobial Agents - Part I

The emergence of antimicrobial-resistant pathogens is one of the most serious public health threats that result mostly from the inappropriate and indiscriminate use of conventional antibiotics for the treatment of infectious diseases. These antibiotics mainly affect bacterial viability, resulting in the emergence of resistant pathogens under this selective pressure. Thus, in turn, necessary to explore the search for novel antimicrobial agents with a novel mechanism of action. The newer class of antimicrobial agents, which target bacterial pathogenesis and virulence instead of affecting bacterial viability, represents an alternate and interesting approach to treating bacterial infections. Quorum sensing (QS) target is one of the main targets among the various antivirulence and anti-pathogenesis approaches since it plays a significant role in the expression of virulence and pathogenesis factors during the infection process. The metabolites or compounds from plants and microorganisms have been reported to inhibit quorum sensing. Due to the extensive diversity and complexity of natural products as compared to conventional antibiotics, they show a wide range of mechanisms of action. The use of natural QS inhibitors or quorum quenchers provides a potential strategy and has been adopted as a model for the discovery of new antimicrobial agents as quorum sensing inhibitors. In this chapter, the advancement in searching for promising novel targets for the development of natural next-generation antimicrobials to conquer infections caused by bacterial pathogens has been discussed in detail.

Emerging resistance to available antibiotics is one of the biggest problems of mankind. This problem brings a serious question to the researcher’s mind: What will be the next promising source of novel antimicrobial compounds to overcome drug resistance? Although many synthetic or modified chemical compounds can be used as a new source of the drug, nature is the richest and most versatile source of new antibiotics. Natural products and their derivatives are far more important in the discovery of new reliable sources of pharmaceuticals. We can use natural compounds and their derivatives to treat cancer, diabetes, and inflammatory and infectious diseases. Other reasons why natural compounds are a good choice for new drug discovery are their lesser side effects, skill to control the existence and development of diseases and potential to act against resistant strains of disease-forming microorganisms. A huge number of diversified chemical components of marine microorganisms, provide us with a rich and versatile source of biologically active components. But among this enormous microbial diversity, very few amounts have been explored till now. Marine microorganisms and their metabolites are reported as an effective and promising sources of new antibiotics or drugs that can act against various antibiotic-resistant strains of pathogenic microorganisms. Marine bacteria, fungi, and cyanobacteria provide numerous industrially useful bioactive components which further possess antibacterial, antifungal and antimycobacterial activities. There are many biotechnological methods and machines like biosensors which is used to detect and isolate useful target components from marine microorganisms. A slight modification in the chemical groups of marine microbes-derive bioactive compounds generates their new derivatives, mimetic and structural analogs that can serve as a novel drug against pathogenic microorganisms. Every structurally different molecule acts functionally with numerous biological activities against various pathogenic microorganisms. This criterion makes marine-derived products more valuable to us in this contemplative time of drug resistance. In this chapter, we discuss various metabolites of marine microorganisms (bacteria, fungi, actinomycetes, and cyanobacteria) having promising antimicrobial properties which could act as a potential natural source of drugs against pathogenic microorganisms.

With the changing environment, microbial pathogens continuously develop antibiotic resistance (AR). As a response to this host-pathogen interaction, host organisms sometimes develop a strategy to stay ahead of the AR developed by pathogens. These molecules are small peptides known as antimicrobial peptides (AMPs). These peptides are short in length, specific in structure and thus have a unique mechanism of action. The uniqueness and specificity in the mechanism come due to the positively charged amino acids which are responsible for initial interaction among AMPs and the negatively charged membrane of the pathogenic cell. Microbes do not develop much ABR against AMPs because of the absence of epitopic regions on AMPs. This property makes AMPs the new therapeutic strategy against microbes. Here, we present a review of the AMPs, their sequence, structure, classification, mechanism of action and the computational strategy developed so far to identify new and improved AMPs that can be used as therapeutic agents.

Endophytes are endosymbionts that live inside the plant without causing any harm. Endophytes could be a fungi or bacteria but the fungal population is widespread worldwide. There are huge chances for exploiting those endophytic fungi for the in vitro production of bioactive secondary metabolites for human welfare. Their successful laboratory cultivation is emerging as a new source of antimicrobial compounds. In recent years, more than 300 endophytes have been isolated from different plant species and successfully cultivated in vitro to synthesize new bioactive metabolites. This phenomenon reflects the chemical diversity of different natural compound classes with their incredible bioactivity. But still, the chemistry and nature of endophytes need to be comprehensively studied. Hence, in this chapter, we have attempted to discuss different endophytes along with their potential antibacterial activities. 

With the recent advances in understanding the role of the gut microbiome and human health, it has become evident that pharmabiotics have huge potential in the therapeutics as well as supplement industries for conditions leading to impaired microbiota. Pharmabiotics can be referred to as a class of microbial therapeutic probiotics which could be live bacterial cells of human origin or their products with clinically proven pharmacological activities found to be beneficial in human disease conditions. So, the mechanism by which bacteria produce synergistic beneficial effects on health could help us to develop a scheme to understand the delicate relationship between the gut microbiome and human health. In this chapter, we will emphasize the role of gut microbiota, the pharmabiotics they produce and how it affects different physiological and metabolic and host-microbe interactions leading to the production of bioactive chemicals with health benefits, eventually leading to the establishment of a healthy immune system. The chapter will also discuss the repercussions of disturbed gut microbiota on overall human health, including host psychiatric health. The fact that pharmabiotics acting as antimicrobial agents will produce no resistant variety is also an added bonus that increases the scope for discovery of such novel therapeutic agents.

The different infections caused by protozoan parasites, such as malaria, leishmaniasis, toxoplasmosis, balantidiasis, trichomoniasis, giardiasis, Chagas disease, amoebic dysentery, are responsible for considerable morbidity and mortality worldwide with desolating social and economic consequences. These protozoan diseases occur all over the world. For the treatment of these diseases, there is a lack of effective, safe, and affordable therapies. Due to the lack of vaccines in most instances and the development of resistant strains to the available synthetic therapeutics, it is important to search for alternative sources of anti-parasitic drugs. Since ancient times, natural products have been used as sources of potential drugs to cure diseases. It has been reported that 80% of drug molecules are natural products. The diversity of natural products can vary, i.e., it may be found in plants, fungi, algae and marine organisms. The plant-based natural products (secondary metabolites), i.e., alkaloids, phenolics, terpenes, and lipids, are potent anti-protozoal molecules. The natural products (secondary metabolites) obtained from microbial origin showed promising anti-protozoal activity. These bio-active molecules 2-(hept-1-enyl)-3-(hydroxymethyl)- 5-(3-methyl but-2-enyl)benzene-- ,4-diol, flavoglaucin, tetrahydroauroglaucin, auroglaucin, 2-(20,3-epoxy-10- 30-heptadienyl)-6-hydroxy-5-(3-methyl-2-butenyl)benzaldehyde, obtained from the fungus Eurotium repens, showed anti-malarial activities even chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Some of the flavonoid compounds, i.e., eupatilin, jaceosidin and nepetin, isolated from the plant Eupatorium arnottianum, showed the highest activity against Chagas disease. The three most important flavonoids, namely kaempferol, (–)-epicatechin and tiliroside showed promising activity against Entamoeba histolytica. The isoquinoline alkaloid berberine is found in several medicinal plants. Berberine salts have profound inhibitory activity against Giardia trophozoites. Two flavonoids, i.e., luteolin and quercetin, isolated from Vitex negunsdo and Fagopyrum esculentum, showed anti-leishmanial activity. An aclerodane diterpene isolated from an ethanolic extract of Polyalthia longifolia displayed anti-leishmanial activity against Leishmania donovani. A novel triterpene Astrakurkurone isolated from the wild edible mushroom, Astraeus hygrometricus, has a definitive effect on promastigote and amastigote form both in vitro and in vivo against L. donovani. Natural products have displayed promising activity against different protozoan infections, but most of these studies on natural products have been performed in vitro only. The transitions from in vitro study to in vivo trials and also the clinical trials of the new compounds are urgently required to prove their efficacy and safety.

Major progress has been made in the last five years to reduce the suffering and death caused by malaria infection worldwide. In the absence of effective preventative tools, such as vaccines, chemotherapy is a principal option to treat malaria. To date, Artemisinin-based combination therapy (ACT) is used as the most effective treatment strategy against malaria infection, which made a significant impact in reducing overall mortality and morbidity. Nevertheless, the current armamentarium of anti-malarial drugs is far from satisfactory as they have unacceptable toxic sideeffects, along with resistance to the conventional treatment regime, emphasizing the need to identify new compounds and alternative treatment strategies to stay one step ahead in this evolutionary arms race between host and parasites. Developing a vaccine would be the most desirable remedy for eliminating this deadliest parasitic disease. Furthermore, immunotherapy can also be the future to treat the inflammatory disease caused by the intracellular pathogen of the genus Plasmodium. In this pursuit, regulation of pro-inflammatory and anti-inflammatory pathways in a correct manner by maintaining optimal Treg/Th17 balance may be the key to successful immunotherapeutic treatment against malaria. In this chapter, the history and mechanism of action of some important anti-malarial drugs have been narrated, along with the future possibilities of potential therapeutic approaches against malaria.

The recent advancements in modern drug discovery as phytopharmaceuticals greatly impact the management and cure of various kinds of fungal diseases. Day by day, the demand for natural, novel anti-fungal drugs is increasing. Natural products are in more demand because they have fewer side effects. The induction of synthetic drugs has diverted researchers' attention toward natural products. Bioactive compounds from different natural sources have immense potential as therapeutic agents as well as antifungal properties. Many of the chemical constituents obtained from nature are easily accessible. The chemical constituents are supposed to be efficient with fewer side effects compared with synthetic drugs to prevent fungal diseases. Phytopharmaceuticals can alter and modulate biological systems without adverse effects and elicit therapeutic benefits. A systematic approach is elaborated in the recent chapter on the basis of their sources, chemistry and the functional aspects of bioactive chemical constituents, along with the recent developments in the field of pharmaceutical technology and research. It also touches upon phytopharmaceuticals as anti-fungal substances, a relatively new trend in drugs. They are acquiescent to transformation into novel dosage forms with relevance against fungal diseases. 

Genus Mycobacterium comprises a group of pathogenic, non-pathogenic and environmental bacteria. The extensive host range of this genus is a remarkable characteristic. Mycobacterium avian complex has a close relationship with nonpathogenic groups and plays a significant role in the evolutionary study of these bacteria. Tuberculosis, a noxious bacterial disease caused by M. tuberculosis, has infected a large section of the population throughout the world, including India. M. tuberculosis is the most successful pathogen of this genus that invades the host as a parasite and survives within the macrophages of its host’s immune-cell lineage. Tuberculosis is of prime concern to clinicians as the development of drug resistance is a common phenomenon of this pathogen. Treatment of patients particularly infected with the multi-drug-resistant and extensively drug-resistant strains are very difficult with the available pool of antibiotics. Some alternative strategies, like the use of novel phytochemicals, synthetic nano-drugs, etc., have proven promising to treat the drugresistant strains.

A spike in the emergence of several viruses is observed in the modern era, including the present SARS-CoV2 virus. The continuous emergence of new viral strains and growing resistance to the existing antiviral drugs urge new drug targets and novel antiviral candidates against them. Host genes utilized by the viruses for their proliferation, also known as host factors, have surfaced as a new antiviral strategy. If affordable to the host cells, targeting the host factors may prove beneficial in controlling viral infection. Host factors play an essential function in the viral life cycle, and modulating their functions would thus impact viral replication. Often, the interacting interfaces between the host and the viral proteins aim at antiviral interventions. This aspect of antiviral drug development is in its inception phase. However, with the advancement in molecular techniques identifying various viral host factors, this field is believed to have immense potential as an antiviral drug targeting strategy. This chapter briefly describes the host proteins' implication in viral biology and how they can be exploited to treat viral diseases.