Current Trends in the Identification and Development of Antimicrobial Agents

Infectious diseases are one of the leading causes of human deaths worldwide. They have devastated human life for a very long time; however, with advancements in diagnostics, prevention, and therapeutic approaches, they were controlled to a manageable extent during the second half of the 20th century. It was assumed that humankind has successfully defeated the threat of infectious diseases. However, many infectious diseases have undergone re-emergence and are now a major cause of concern. Besides, there is the emergence of several new infectious diseases. These diseases are termed re-emerging and emerging infectious diseases, and collectively account for more than 20 infectious diseases. World Health Organization has identified these diseases as the predominant health hazard faced by human beings. Owing to this situation, there is an urgent need to revisit infectious diseases and make efforts towards the development of anti-microbial drugs for emerging and reemerging microbial diseases. The present book chapter aims to provide a comprehensive account of re-emerging and newly emerging infectious diseases and the paradigm shift of antimicrobial drugs in the 21st century. It is expected to provide useful insight into this important research and development area.

Increased incidences of multidrug-resistant (MDR) microorganisms has become a global health concern for humans, animals, and agriculture. The advent of newer resistance mechanisms evolving in microorganisms at a high rate compared to the treatments available urges the need to understand its origin and reservoirs. The expanded use of antimicrobial drugs, inefficient diagnosis as well as broad use in agriculture and veterinary contributes to the emergence of resistance in microorganisms. Presently, almost all infectious agents (bacteria, fungi, and viruses) have developed MDR. About 7 lac people die of bacterial resistance to antibiotics every year, with an estimated ~10 million deaths by 2050. Similarly, MDR arising in pathogenic fungi like Candida, Aspergillus, or Fusarium to the limited therapeutic options is highly challenging. Bacteria and fungi develop resistance mainly due to biofilm formation, increased efflux pump activity, drug target mutations, drug binding alterations, chromosome abnormalities, and the ability to escape host immune defenses. The co-existence of MDR bacteria and fungi forming biofilms is even much of an alarm in medicinal applications. Apart from these, drug resistance to current antiviral therapeutics has imposed significant risk amidst life-threatening diseases caused due to viruses like HIV and influenza A. Owing to its severity and complexity, we aim to illustrate the detailed mechanism and evolution of MDR in bacteria, fungi, and viruses. We also review different approaches to deal with MDR, emphasizing alternatives, vaccine development, global surveillance programs and stewardship measures to combat resistance.

Drug discovery and development is a complex and lengthy process aimed at producing therapeutic substances that can be both effective in terms of pharmacological activity, specificity, good affinity to its target molecule, and safe for humans. It is a necessary step due to many emerging diseases of microbial, parasitic and genetic diseases affecting the entire world so that effective prophylaxis and treatment could be provided. The successful process of discovering a new drug relies on proper discovery and characterization of the lead compound followed by the preclinical studies that ascertain the safety and efficacy of the newly discovered compound. A number of information gathered from preclinical studies that, include information about the formulation, dosage, delivery, pharmacokinetic, pharmacodynamic, mode of action of the drug as well as its relation with other drugs when they interacted, could determine the fate of the new drug’s approval by the regulatory agency for a clinical trial on humans. Human clinical trials with the new drug under investigation are carried out on volunteers in different phases with a common goal to ascertain the new drug's safety, efficacy, and possible side effect in the actual environment. Since the human body is more dynamic, optimal dosage and effect of other substances on the drug itself are determined so as to ensure better treatment; satisfactory results from the human trial could pave the way for application and approval for a human trial in phase IV where the drug may subsequently go for commercialization but with strict monitoring for any unforeseen side effect most especially in a vulnerable group. Although this is an expensive, tedious and risky process for the pharmaceutical industry and volunteers, which takes many years, it is necessary. This chapter discusses the necessary steps for developing a new drug from the initial discovery from bench-top up to human trial and commercialization as an over-the-counter drug. 

The discovery of penicillin opened the avenues for antibacterial drug discovery to address the global problem of deadly infectious diseases. However, despite the availability of potent antibiotics and effective vaccines, bacterial infections are still the major contributors to morbidity and mortality worldwide. The use of antibiotics is a two-edged sword; on the one hand, antibiotics have helped us combat deadly bacterial infections. On the other hand, overuse of antibiotics has led bacterial pathogens to develop drug resistance. The components of the bacterial cell-like cell wall, cell membrane, protein synthesis, and nucleic acid synthesis were targeted to develop effective drugs. Using these selective microbial targets, multiple potent antibiotic classes were developed in the last century, but emerging bacterial resistance and a decline in the number of new antibiotic approvals in recent years are pushing us back to the pre-antibiotic era. An increase in multidrug-resistant strains and the ineffectiveness of current drugs pose a challenge for researchers to develop new antibiotics with a novel mechanism to treat drug resistance. In the current chapter, we focus on the antibacterial drug used for the treatment of important human pathogens.

Fungal infections are one of the major causes of fatalities worldwide, causing an estimated 1.5 million deaths annually. Over the past few decades, the incidences of fungal infection have risen with the increase in the cases of immunocompromised patients. However, the impact of fungal diseases on public health is often underestimated. These infections are predominantly caused by the Aspergillus, Candida, and Cryptococcus species. Current therapeutic approaches to treat such fungal infections are limited to five distinct classes of antifungal drugs, viz. polyenes, echinocandins, azoles, pyrimidine analogs, and allylamines. Moreover, a few synthetic molecules are also used as fungicidal agents. Despite the current antifungal armamentarium, the burden of fungal infection is exacerbated by the emergence of drug resistance, host toxicity, and negative interactions with other drugs. The paucity of new antifungal drugs has further complicated the treatment of fungal infections. These limitations provide a rationale for developing novel antifungals preferably with new mechanisms and molecular targets. This chapter thus summarizes the currently used antifungal drugs, their effective combinations, and the challenges inherent to the development of new antifungal drugs. The chapter also addresses strategies to bolster the antifungal pipeline involving emerging new targets for better management of fungal infections.

Antiviral drug discovery and its developmental processes happen to be the need of the hour. The break-out burden of complications and mortality caused by viruses like Influenza, Ebola, MERS, SARS and presently, the subtype SARS-CoV-2 are randomly growing in an exponential arc. Under such critical circumstances, there occurs an urgent paradigm shift in the research domain where antimalarial drugs like Hydoxychloroquine were given as a prophylactic treatment to improve the condition of the patients affected by the SARS-CoV-2-COVID-19 disease. For the use of emergency purposes in this global pandemic, a ground breaking development has taken place in vaccine therapy with mRNA-based technologies by pharma giants like Pfizer- BioNTech, Moderna Inc. and AstraZeneca Plc. All three newly launched successful mRNA vaccines, like Comirnaty, mRNA-1273 and AZD1222, in their late-phase clinical trials showed an effective rate up to ~ 95%. Many alternative approaches use translational medicines and artificial intelligence tools to mitigate clinical morbidities within a given timeframe. Hence in this particular book chapter, we tried to highlight the pros and cons of all the possible antiviral drug interventions and strategies that have been implemented from the past till the present to combat several epidemics and global pandemics. At present, the occurrence of the COVID-19 pandemic imposed a greater threat and unprecedented challenge in the antiviral drug discovery platform that needs to be focused on in detail.

The existence of substantial evidence about the development of resistance to a drug among microbes has gained a lot of attention from the scientific world. To address this problem, researchers have been conducting experiments and testing strategies, including screening various molecules and using plant-derived natural products to ascertain if these substances can serve as an untapped source of antibacterial, anti-viral, and anti-fungal agents. The non-toxic, non-synthetic, causing minimal side effects, and cost-effective nature of these substances make the development of new anti-microbials heavily dependent on the use of many of these existing products and increase the demand for finding new natural products that are yet to be discovered. These plant-based natural products offer great promises to provide the best protection against infections and pathogenesis in many diseases. Furthermore, the biodegradable nature of many of these products increases their chances of being chosen by farmers and plant biologists to use to combat microbial pathogenesis. This chapter covers the current insights on the conflicts and opportunities of popular plant-derived natural anti-microbial compounds containing a reservoir of secondary metabolites, viz.. flavonoids, alkaloids, terpenes, coumarins, phenols and polyphenols. The chapter lists natural vegetable products, which serve as potent anti-bacterial and anti-fungal agents, and describes various plant extracts, which exhibit bacterial quorum sensing, biofilm as well as efflux pump inhibitory activity. Previous studies have demonstrated the effectiveness of these plant-based natural products in the treatment of neurodegenerative diseases as well. This chapter also summarizes the neuroprotective activity of these products and their potential to serve as therapeutic agents to block or delay the progression of disorders.

In recent years, the antimicrobial resistance to various synthetic or chemically formed antimicrobial agents in medicines and food products has been observed. The high preference of consumers for purchasing food products free from chemical preservatives has led to more exploration into using antimicrobial agents from natural sources like plants, fungi, algae, and bacteria. The marine ecosystem comprises microorganisms, plants, vertebrates, and invertebrates that are rich sources of diverse antimicrobial products and can be a significant potential for developing novel type therapeutic agents, as the major portion of the sea has still not yet been examined for the evaluation of natural molecules for their antimicrobial activity. Such marine ecological niches promise a great source of antibacterial agents against many drugresistant strains of pathogenic microorganisms. Among the marine source, marine algae are a diverse group of organisms that includes brown, red, and green algae that have been targeted over the last few years for the secondary metabolites and a broad range of natural molecules for a broad spectrum of bioactivities beneficial to humans. Such bioactive compounds and secondary products possess a broad range of biological activities of antibacterial, antiviral, and antifungal properties. The class of compounds derived from marine algae, such as polysaccharides, fatty acids, phenolic compounds, pigments, lectins, alkaloids, terpenoids, and halogenated compounds, would be a new emerging area for unconventional drugs. Such classes of compounds will share a potent ability to control new diseases or tackling against multi-resistant strains of pathogens.

There is an urgent need to search for effective novel antibiotics due to the evolution of pathogen resistance towards the existing anti-microbial drugs. To fulfill the demand of pharmaceutical industries for novel drugs against pathogenic microbes, the potential source is nature, which is the largest repertoire for discovering biologically active drugs. Among the natural products, mushrooms are primary sources of diverse low and high-molecular-weight compounds that demonstrate anti-bacterial, anti-fungal, anti-parasitic and anti-viral activities. Mushrooms belonging to basidiomycetes or ascomycetes were classified into edible and non-edible and had high nutritive and medicinal properties due to the presence of bioactive compounds. The most common edible mushrooms comprise Agaricus bisporus, Lentinus, Auricularia. Hericium, Grifola, Flammulina, Pleurotus, and Tremella are potent sources of vitamins (thiamine, riboflavin, niacin, biotin and ascorbic acid, Vitamin A and D), lipids (mono, di, and triglycerides, sterols, phospholipids) and polysaccharides whereas non-edible mushrooms Ganoderma lucidum (Reishi), Lentinus edodes (Shiitake), Inonotus obliquus (Chaga), Ganoderma, Trametes, Cordyceps spp., etc., are potent sources of alkaloids, terpenoids, steroids, anthraquinones, benzoic acid derivatives, and quinolines. The literature review suggests that mushrooms showed high anti-microbial activities against Gram-positive bacteria (Bacillus spp., Listeria monocytogenes, Micrococcus spp., Staphylococcus spp. etc.) and Gram-negative bacterial species (Escherichia coli,Klebsiella spp. or Salmonella sp) as well as anti-fungal (Candida spp., Aspergillus spp., Penicillium spp. etc.) and anti-viral (HIV-I, influenza) activities. The present chapter highlighted the mushrooms showing anti-microbial activity, techniques for appraisal of anti-microbial activity, anti-microbial bioactive compounds and last but not least, the downstream process of some selected compounds originally isolated from mushrooms.  

The development of drug resistance in microorganisms has become one of the greatest global health challenges, as microorganisms tend to adapt to organic drugs via several mechanisms. Multi-drug resistance (MDR) in microorganisms not only increases the mortality rate of humans, but clinicians are also running out of options to treat MDR infections. A solution to this problem could be found in inorganic chemistry, where metal elements are converted in to nanoparticles that function as both drug and drug delivery agents to control microbial growth and overcome the resistance imposed on organic drugs. Nanoparticles have a high surface area to volume ratio, making them highly reactive with selective types of molecules such as bacterial/fungal cell walls. This makes nanoparticles an effective alternative to traditional chemical drugs. The development of resistance in the case of nanoparticles is almost nil. Nanoparticles of various elements have proven to be effective anti-microbial agents with several other pharmaceutical activities. Nanoparticles are also effective drug delivery agents that increase the bioavailability of drugs, enhance bioactivity, and increase drug flux into and through skin and biofilms. This chapter provides a compilation of various types of organic and inorganic nanoparticles, with their bioactivity, mode of action, synthesis, side effects, and mode of administration. Different types of nanoparticle-based drug delivery systems are summarised in this chapter, along with a summary of their organ-specific drug delivery. This report can provide a detailed understanding of nanoparticles in anti-microbial applications and aid in R&D to yield future nanomedicine.

With the escalating concerns about antimicrobial resistance and the intractable nature of microbial infections, there is a demand for the expansion and development of alternative stratagems for treating microbial diseases. At present, the advent of antimicrobial resistance amidst microbial pathogens, especially the ‘drugresistant’ ones, has led to poor clinical consequences, thus, shooting up healthcare outlays and mortality. Moreover, the formation of biofilms-like assemblies by microorganisms and their surface association mechanisms have led to secondary infections in immunocompromised individuals and further muddled the prophylaxis. Such microbial resistance is primarily attributed to the inapt and undue use of antimicrobials in humans/animals and the unregulated administration of these drug formulations. Therefore, there is an urgent need to propose and imbibe various modern, multifaceted antimicrobial formulation approaches to prevent the fatal consequences of antibiotic resistance and enhance the effectiveness of microbial growth control. Currently, several new-age antimicrobial formulation therapies are being explored and have shown promising results as efficacious preventatives, diagnostics, and drug carriers in comparison to conventional antibiotic therapy being used. In this chapter, we highlight the different categories of new-age antimicrobial formulation therapies currently in use, their molecular mechanism of microbial targeted delivery, their effectiveness over the traditional therapies, the challenges in their development and the future outcome of these contemporary formulations.

Antimicrobials help to restrain or fix the arising irresistible infection in a superior manner anyway, and living creatures require another class of antimicrobials. The new classes of antimicrobial development for the emerging and reemerging pathogenic microbes, the evolution of multidrug-resistant microbes, and the threat of bioterrorism or bioweapons are a global necessity. Integrative genomics, proteomics, and immunoinformatics are powerful tool approaches to design and develop antimicrobials promptly and economically. Natural and artificial antimicrobials for humans, animals, and avians are designed and developed using various immunoinformatics databases, tools, and algorithms. Immunoinformatics plays a great role in dissecting and deciphering genomics, proteomics, and clinical enormous information effectively. The artificial neural network, quantitative matrices and support vector machine algorithms based on immunoinformatics tools would be strong for the planning of adequate customized antimicrobials. The immunoinformatics strategies for antimicrobial improvement are staggeringly utilized for improving living creatures' well-being. The usage of artificial intelligence and machine learning tools is also an asset for immunoinformatics way of antimicrobial design and development. In the new time of pandemic illnesses, progressed immunoinformatics devices play a great role in improving antimicrobials.