Frontiers in Anti-infective Agents

About one-third of the world’s population is infected with a deadly communicable disease called Tuberculosis (TB), caused by Mycobacterium tuberculosis. A majority of this infected population is confined in South-East Asia, especially India. With the emergence of multi-drug resistant (MDR) strains through the sequential accumulation of chromosomal mutations, the disease has become the 9th leading cause of death worldwide. The need of the hour is to discover new antiinfective drugs that have low toxicity, potent activity, are cost-effective, and have a novel target against the MDR M. Tuberculosis strain, to combat the dreaded disease. Actinobacteria can be a good candidate for the discovery of new anti-TB drugs as they are prolific producers of antibiotics that can be used for the treatment of different infectious diseases. The exploration of anti-infective agents from soil actinobacteria is exhausting, and the frequency of extracting novel compounds is declining because of the redundancy in the isolation of bioactive actinobacteria. Nevertheless, there is great prospect for the discovery of effective anti-TB drugs from actinobacteria that are isolated from unique, extreme and unexplored/under-explored ecosystems, such as marine, cave, endophytes from medicinal plants, etc. Anti-TB compounds extracted from actinobacteria, especially Streptomyces sp., associated with medicinal plants, marine etc. display good activity against MDR M. tuberculosis and low toxicity towards macrophage and normal cells. Further exploration of new anti-TB agents from novel and rare actinobacteria from unique, extreme and unexplored/under-explored ecosystems that have a novel target against MDR strain, is the need of the hour to suppress the dissemination and development of TB.

Our book chapter discusses the two most important protozoan and helminth infections: Leishmaniasis and Elephantiasis. Both of these communicable diseases are a major concern for tropical and subtropical countries. Leishmaniasis has been responsible for frequent epidemics, while elephantiasis is the second most important vector borne disease after malaria. Here, we discuss in detail the vectors transmitting these diseases, the mode of transmission, disease pathogenesis, and conventional/ target based therapeutic approaches.

AIDS (Acquired immune deficiency syndrome) is caused by the retrovirus HIV (Human immune deficiency virus). HIV destroys T-cells which provide cellmediated immunity (CMI) to human beings. Like other viruses, HIV has a protein capsid and a core RNA genome. HIV infection causes severe damage to the immune system making it vulnerable to various infectious pathogens when the damaged immune system fails to fight the infection, resulting in the advanced stage called AIDS. Two types of HIV exist. HIV-1 is the causative organism of HIV infection worldwide with around 90% of infection. HIV-2 has been reported in a small group of people in western Africa. Both HIV-1 and HIV-2 lead to AIDS in their advance stages. The treatment of HIV infection and AIDS is a big challenge to medical sciences. Many drugs are available that can be used against HIV infection and AIDS. These drugs are known as antiretrovirals (ARVs). ARVs prevent replication of HIV inside the host cell gradually slowing down the progress of HIV infection. Therefore, antiretroviral drugs can prevent AIDS-related complicated diseases and prolong longevity. However, it does not fully restore health. The potential effect of HIV on our health is clearly exhibited by many immunologic abnormalities that occur despite effective suppression of HIV replication by ARVs. The cure for AIDS is still a distant future.

Peptides are short chain amino acids having low molecular weight usually less than 20 kDa. Peptides having health beneficial biological activity are known as bioactive peptides (BP). BP may be free or encrypted within the protein sequence and encrypted peptides are active only when released from the parent protein. Enzymatic hydrolysis and microbial fermentation are the most common methods for the production of BP from the parent protein. BP have numerous beneficial biomedical functions. They can act as antihypertensive, antioxidant, angiotensin converting enzyme inhibitors, and antimicrobial agents. With the emergence of new infectious diseases and multidrug resistant pathogenic bacterial strains, there is an urgent need for the discovery of new antimicrobial agents having a broad spectrum of activity. In this context, BP having antimicrobial activity (antimicrobial peptides) can be a potential candidate for the development of new antimicrobial drugs. Antimicrobial peptides (AMPs) have played an important role in the innate immune system of plants and animals. Hence, various AMPs have been isolated from microbes, plants, and animals. AMPs can directly or indirectly kill the pathogen and their mechanism of action is different from conventional antibiotics. They also have immunomodulatory functions. Moreover, AMPs have lower pathogen resistance as compared to conventional antibiotics. These properties attract researchers and pharmaceutical industries toward the development of AMPs as new anti-infective drugs against the multi-drug resistant pathogens. The present chapter highlights the production and application of BP as well as their potential use as antimicrobial drugs.

The emergence of drug resistance in many bacterial pathogens and the rise of fungal infections have caused a resurgence of interest in finding new reserves of bioactive compounds. The increase in resistance to conventional antibiotics by many bacterial pathogens may be due to the decline in the discovery and development of novel antibiotics. Superbugs are those microorganisms (pathogens) that are resistant to the commonly used antibiotics. The World Health Organisation (WHO) has published a list of twelve potentially most dangerous priority pathogens with antibiotic resistance in 2017 and emphasized on discovering new antibiotics to tackle these pathogens. ESKAPE pathogens comprising Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa and, Enterobacter species can productively escape the antagonistic effects of the current antimicrobial agents. Urgent discovery of new drugs to tackle these resistant pathogens is required. This chapter mainly focuses on the strategies and methods on discovering novel antibiotics against drug resistant pathogens.

Fungi are versatile organisms that cause infectious diseases to millions of people. The disease caused by fungi are rapidly rising in immunocompromised patients. Commonly available antifungal drugs act on the cell wall and nucleic acid synthesis and, cell division. However, excessive use of the clinically available common antifungal drugs has led to the development of multidrug-resistant strains that no longer respond to treatment. The rapidly emerging multidrug-resistant Candida auris has caused severe infection and has become a serious burden on public health. Therefore, the search for new effective compounds especially from endophytes associated with medicinal plants that have a novel target and mechanism of action against the multidrug-resistant strains to combat the rapidly emerging infectious diseases caused by fungi, has become vital.

The emerging infectious human viral diseases have been a prime concern for public health since the last decade. Various new viruses or virulent strains of old viruses have emerged during this period. Appropriate knowledge of the viral pathogenesis is required to understand their emergence and possible therapies. Various factors are involved in the emergence of viruses and new human diseases. Some of these human diseases are zoonosis. Zoonosis can be defined as human diseases caused by animal pathogens, which that are transmitted to humans. The WHO has been continuously updating the prioritizing list for various infectious, and emerging viruses. In this chapter, we discussed some important emergent viral pathogens, such as Ebola virus, Crimean-Congo Haemorrhagic Fever virus, and Marburg virus, Hanta, Hendra, and SARS. Detailed understanding of the emergence, the modes of transmission and pathogenesis, and possible treatment plans are necessary to check the invasion and outbreak caused by these viruses.

Leprosy, also called Hansen’s disease, is known since ancient times. It is a curable, slow, progressive lifelong contagious disease, caused by an intracellular, rod shaped, aerobic, slow growing bacterium, Mycobacterium leprae. Leprosy affects the skin, peripheral nerves, and mucosal portion of upper respiratory tract and may also affect other organs. Leprosy is not critically contagious. Early diagnosis and treatments prevent nerve involvement, which is considered to be the hallmark of leprosy. Its diagnosis is carried out from a number of distinct clinical presentations which should be complemented by skin bacilloscopy and histopathology. Highly effective MDT (multidrug therapy) is used as a medication which aims to eliminate the causal organism in the shortest possible time. It involves three major drugs: dapsone, rifampicin (Rifadin), and clofazimine (Lamprene). The WHO has been providing free treatment for all people suffering from leprosy since 1995. This chapter focuses on the clinical and diagnostic features of leprosy as well as the current drugs used in the treatment along with their pharmacokinetics.

Silk sericin is a glycoprotein which surrounds and keeps two fibroin filaments together. It is produced in the middle silk gland during the fifth instar of the larval stage of the silkworm. During the process of degumming, sericin is removed from the silk cocoon. This waste sericin has been discovered to have a wide variety of applications as antioxidant, antityrosinase, wound healing, anti-wrinkle agents, etc. Sericin from various silk cocoons was also found to have antimicrobial activity against several fungal and bacterial pathogens. Sericin with antimicrobial activities can be used in various applications such as in the preparation of wound healing gels, and the treatment of fabrics for medicinal purposes. A particular study showed the application of sericin as a coating material on polyester or polyamide fibres, to be used as media for air filters. It reduces the free radicals in the filter media and contamination of fungi and bacteria, thus helping in purifying the polluted air. Hence, the biodegradable and biocompatible nature of silk protein sericin makes it a potentially promising substitute of various antibiotics and certain other harmful antimicrobial agents that we use in our daily life.

Human beings and the microbial world have co-existed and maintained a symbiotic balance; providing a protective and stabilizing effect on the body as resident microbes. Pathogenic bacteria invade and grow in human tissues causing diseases and damaging the body. They represent a major problem threatening the health of humans, sometimes leading to death. This stimulated the scientists to find new solutions to many diseases by clarifying the interactions of antibacterial compounds with the biological medium. The use of antibiotics protects the body from pathogenic microorganisms, however, there are also some side effects. Proper characterization and adequate understanding of the mode of action of antibiotics are, therefore, an indispensable necessity. Examining the mechanism of action of the various antibiotics illustrates how they are effective against pathogenic microorganisms with minimal selectively. The mechanism of action of antibiotics occurs in the cell wall or within the cell of pathogens where it may block the synthesis or break down the cell wall, block catabolic energy-supplying mechanisms or anabolic protein synthesizing processes. Hence, in this chapter, the classification of antibiotics, their mode of action, application and, how antibiotics are used as anti-infective agents will be discussed.

Malaria is an infectious disease. Many anti-malarial drugs have been introduced to eliminate malaria. Earlier, the major antimalarial drugs were natural products but in due course synthetic drugs have replaced them. Pursuing multiple strategies is needed for discovering new drugs for malaria. Global International Centers of Excellence for Malaria Research (ICEMR) network is conducting many research studies. The research activities include clinical studies for assessing antimalarial drug efficacies, drug susceptibilities of parasite isolates and determining resistancemediating parasite polymorphisms. There are several approaches for the discovery of new drugs. The approaches should also focus on low cost and novel therapies. Currently, the available drugs are optimized in many ways using combination therapy and the discovery of compounds from plants. This chapter focuses on the available antimalarial medications, including both synthetic and natural products. The present chapter also highlights indigenous medicinal plants, which can be potentially used for the development of antimalarial drugs.