Frontiers in Anti-Infective Drug Discovery

Neurodegenerative diseases (NDs) have a serious impact on global health with no effective treatments yet available. Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disorder, considered to be the most common cause of dementia. There is increasing evidence for the infectious/inflammatory etiology of AD. Although brain is assumed to be an immunologically isolated organ, many bacteria (Helicobacter pylori), viruses (Herpes simplex virus, influenza, CMV etc.), fungi, toxoplasma, are associated with AD. The presence of immune-related antigens around amyloid plaques, activated complement factors, cytokines and a wide range of related receptors in the brain of AD patients, led to the concept of “neuro-inflammation”. Persistent or acute neuronal and peripheral inflammatory response to infectious agents is gradually gaining more attention, as a risk factor for someone to develop sporadic AD. The human microbiome (HM) has a pivotal role in nutrition, health and disease. About 100 trillion bacteria from up to 1000 bacterial species inhabit the gastrointestinal (GI) tract, contributing, at least in part, to what is known as the “human-biochemical” or “genetic-individuality” and resistance to disease. Several pathologies, including AD and inflammatory bowel disease, are associated with alterations in gut microbiome. Microbes of the gut microbiota or of extracorporeal origin possess the ability of producing functional amyloid proteins. These amyloids, via lymphatic and systemic transport to the Central Nervous System (CNS), seem to have an important role in the expression of neurologic and psychiatric disorders, such as schizophrenia, anxiety and AD. Cross-seeding of the neurodegenerative disorder proteins may be induced by these amyloids. Moreover, chronic inflammatory response to these immune-reactive proteins can also be an important risk factor for CNS well-being. Therapeutic/preventive options for halting CNS disorders’ onset, could include: (a) Anti-inflammatory, anti-amyloid drugs (β-sheet breakers and other inhibitors of amyloid fibrillization), monoclonal antibodies, nanoparticles, which target pathological components of AD, or other medical interventions to remove infectious agents or to ameliorate their biochemical influence on GI-CNS tract, (b) Prebiotics to enhance the growth of desired organisms and reduce oxidative stress - a cause that has been implicated with AD, (c) Probiotics to provide both the desired bacteria, which increase the competitive effects with pathogens, and essential metabolic products, and to modulate the host immune system to resist in infection (d) The consumption of natural products, and the dedication to the Mediterranean (MeDi) and Asian (AsDi) Diets, abundant in bioactive compounds, are capable to prevent AD or reduce danger of AD, and strengthen the host's ability to confront infections. The significance of diet diversity leading to the microbiota diversity is a new clinically important concept. Finally, and (e) preventive medical and/or other therapies to alter the amyloids produced by bacteria, to decrease their production or stimulate their removal. This chapter is addressed to, and urges the excellent cooperation between experts of neurology/psychiatry, microbiology, biochemistry, dietary and nutritional sciences, in order to confront AD.

Malaria remains one of the most dreadful diseases affecting millions of people across the world. It is an infectious disease spread through the (female anopheles) mosquito caused by the parasitic protozoans belonging to genus Plasmodium. The most lethal species is Plasmodium falciparum which if left untreated, may cause organ failures (severe malaria) or may accumulate in brain (cerebral malaria) causing coma and finally leading to the death. The disease is mostly prevalent in Sub-Saharan Africa. Children under the age of 5 years, pregnant women and travellers to the malaria prone area are particularly at higher risk of getting malaria. It is typically diagnosed by microscopic examination of blood using blood film or antigen-based rapid diagnostic tests. The treatment of malaria comprises various synthetic, natural analogues administered orally or parenterally. The choice of therapeutic agents depends on the species of parasite, pattern of resistance and the seriousness of the infection. Emergence and spread of the multidrug resistant strains of the causative organisms has extremely limited the choice of antimalarial chemotherapeutics. Only limited treatment options are currently available due to the resistant species highlighting the need of efficient research for developing newer broad spectrum antimalarial drugs. The discovery of potent vaccine against malaria still remains a major challenge amongst scientific community, with only limited success achieved till now. The choice of the delivery system plays a vital role in determining fate of the drug as it’s not only important for delivering the right drug at the right site, but also it can minimize the untoward effects of drugs. Nano-carriers or nanosystems are useful tools that are particularly gaining distinctive attention in malaria chemotherapy because of their ability to minimize the side effects, improve bioavailability and the selectivity of the drugs by altering the biopharmaceutics and pharmacokinetic property of the drug molecules. Discovery of potent drugs like Arteether (ART) and Bulaquin have been some major breakthroughs in antimalarial research. However; the major challenge in management of malaria in the current scenario is to combat drug resistance and to develop new potent drugs in order to completely irradiate this fatal disease. This chapter is intended to highlight on some basic aspects of malaria, challenges in current chemotherapy, current investigations towards malaria chemotherapy and vaccine, and the use of nanotechnology as a promising strategy for malaria treatment.

This chapter aims to review the literature on anti-infective (also known as antimicrobial) drugs among the anti-infections drugs, and to highlight recent developments relating to novel antibiotics and their classification. Antibiotic classification is determined according to their structure and mechanism of action; the main groups include β-lactams, macrolides, fluoroquinolones, tetracyclines, and aminoglycosides. Despite significant progress in anti-infective therapies, infectious diseases caused by bacteria and fungi remain a major worldwide health problem due to the rapid development of resistance to existing drugs. This resistance increasingly limits the effectiveness of current anti-infective drugs. To overcome this problem, scientists are searching for novel therapeutic agents that are efficacious against microorganisms and cause limited side-effects. Naturally occuring compounds in plants have previously been used successfully to treat many types of infection and illness. For this reason, it is quite important to understand the chemical composition of natural products and their mechanisms of action, in order to synthesize semi-synthetic or synthetic anti-infective drugs. Indeed, many chemically synthesized drugs originated from natural sources, e.g. aspirin (willow plant), opioids such as morphine (opium poppy), atropine (Atropa belladonna), and quinine (cinchona). Therefore, nature is a very fruitful source for pharmacy, medicine, biology and chemistry students.

In 2015, an estimated 10.4 million people were infected with and 1.8 million people were killed by tuberculosis (TB). Multi-drug resistant (MDR) and extensively drug resistant (XRD) TB were other reported complications in the treatment of TB. Almost 3.3% of new TB cases and 20% of previously treated cases have multi-drug resistance (MDR) TB while 9.7% of people with MDR-TB have XDR-TB. Recently, two chemical entities, namely bedaquiline and delamanid were granted conditional approval for the treatment of MDR-TB, and are recommended only to those patients for whom other treatments fail to cure. The diagnostic platform, including GeneXpert Omni® and Xpert Ultra® is in development. There are seven new compounds and eight approved or repurposed antitubercular drugs in advanced phases of clinical trials, while thirteen vaccine candidates are in clinical trials. New diagnostics, anti-tubercular drugs and tubercular vaccines will be needed to achieve the targets set in the End TB strategy. This chapter explores the medicinal chemistry of anti-tubercular agents in various phases of clinical trials. The present chapter also deals with various diagnostic technologies for early detection of tuberculosis, as well as the tubercular vaccines in various phases of clinical trials.

Widespread outbreak of numerous infectious diseases across the globe has created awareness in chemists for the novel design and synthesis of lead molecules. Like hepatitis is one of the viral infectious disease, damages the liver function and therefore causes major complications, even leads to death in many cases. More than one third population of the world is affected by hepatitis. Different viral hepatitis are Hepatitis A (HAV), B(HBV), C(HCV), D(HDV) and E(HEV), depending upon the infecting virus type. Hepatitis A and E viruses are usually contacted after eating and drinking contaminated food and water. While, HBV, HCV and HDV are transmitted through contaminated blood. Hepatitis B and C are typically chronic, but HDV may be acute or chronic in nature. Non-viral hepatitis are also reported either due to alcohol consumption or metabolic disorder medications, which causes the liver stress or inflammation. The treatment options of hepatitis vary depending upon what form you have and what caused the infection. Until recently, the treatment of hepatitis B has been reported with interferons alone or pegylated interferons while hepatitis C with interferons only or pegylated interferon (PEG-IFN) and ribavirin in combination, both are less successful (35-40%) and have side effects. Thus, a virus-specific, efficient and drug resistant free, anti-HBV and anti-HCV therapeutics are needed. Since 2011, the use of new drugs in targeting NS3/4A protease, NS5B polymerase and NS5A enzymes have enhanced treatment rates (70-90%) but still showed some side effects. Furthermore, inhibitors are at diverse stages of clinical development for NS5B and NS5A polymerase targets. Future design and synthesis of novel drugs must address genetic difference in HBV and HCV with least drug resistance. Also, for the genetic over-expression in HCV, a number of investigational techniques have developed which led to the comprehensive analysis of different aspects of viral life-cycle and interactions between virus and host (human). Thus, a rising list of targets for therapeutic involvement has been revealed. The directly acting anti-virals (DAAs) is another therapy method which helps in exploring novel and highly developed combinations of drugs. In this chapter, we discuss the synthetic advances of receptor based anti-viral scaffolds in hepatitis, which afforded significant numbers of agents such as drugs or drug leads, their mechanisms of action (MOAs), structure-activity relationships (SARs) and future structural perspectives as drug candidates.

The formation of biofilms contributes significantly to bacterial resistance to antibiotics, innate host defences and in persistent infections. In this era of multidrugresistant bacterial infections, the discovery of novel antibacterial agents is required to treat infections that kill these organisms via novel mechanisms of action. Antimicrobial peptides, also known as host-defence peptides are short polypeptides (<40 amino acids) and are an integral part of the innate immune system that protects a host from bacterial infection. This chapter discusses the potential of anti-microbial peptides as an antiinfective agent, its advantages, disadvantages, their structures and mechanisms of action. A perception of the bacteriostatic and bactericidal mechanism of antimicrobial peptides is required to facilitate the rational design of novel antimicrobial agents. Thus a deeper understanding of the mechanism of natural AMPs will also aid in developing new antibacterial agents. Furthermore, the chapter also considers the possibility of the use of synthetic antimicrobial peptides containing both natural and unnatural amino acids as anti-infective agents. Apart from the antibacterial property, AMPs are also being used as drug delivery vectors to transport the cell impermeable drugs to the cell interior. The diversity and broad spectrum antimicrobial activity of AMPs along with its multidimensional properties could be exploited as a potential and promising drug candidate.