Frontiers in Anti-Infective Drug Discovery

This chapter is an updated review of the literature published since 1980s about compounds with antiviral properties isolated from red seaweed (Rhodophyta). It integrates findings from molecular, experimental and cellular researches to show an overview of potential antiviral agents derived from Rhodophyta and their promising application in viral therapy. Extracts of and/or compounds isolated from red seaweed, mainly polysaccharides, play a protective role against different viruses such as human immunodeficiency virus, herpes simplex virus, influenza virus, cytomegalovirus, and others. The main target of the antiviral action of these algal compounds is the initial binding of pathogens to the host cells.

The continued evolution of multiple drug resistant organisms associated with common bacterial and fungal infections have become a critical and life threatening challenge facing modern medicine. To overcome this challenge new therapeutic agents that kill these organisms via novel mechanisms of action must be developed. Antimicrobial peptides offer several advantages as potential therapeutic agents against multiple drug resistant organisms. Their greatest advantage is their unique mechanism of action which involves first the disruption of the target’s cell membrane followed by lysis of the cell thus causing cell death. However, natural antimicrobial peptides also have several inherent disadvantages these included low metabolic stability, lack of bacterial strain selectivity and toxicity toward human cells. In this chapter the development of synthetic antimicrobial peptides containing both natural and unnatural amino acids as well as peptidomimetics designed to address these disadvantages will be discussed. An overview of the physicochemical properties required for antimicrobial activity will be presented with emphasis on the logic of the process of designing new antimicrobial peptides. Specific examples of synthetic antimicrobial peptides will be presented to highlight the application of various approaches to address the issues of metabolic stability, increasing the selectivity for prokaryotic verses eukaryotic cells, as well as increasing bacterial strain selectivity and potency. In addition the chemical analysis methods of Circular Dichroism spectroscopy (CD), isothermal calorimetry (ITC) and fluorescence spectroscopy to monitor calcein induced leakage from liposomes will be discussed. These techniques provide physicochemical information concerning peptide-lipid interactions which provide critical insight for the design of therapeutically useful antimicrobial peptides.

Natural products have historically been a rich source of the active ingredients of drugs, especially as anti-infective agents. Natural products provide valuable scaffolds for lead optimization since they are potent, soluble, bioavailable, targeted therapies for many indications. In the wake of a de-emphasis of natural product research in the private sector, the current pipeline for anti-infectives is dwindling. New technologies in natural product isolation, synthesis, and screening in the post genomic era have provided valuable new leads for drug discovery. This chapter describes anti-bacterial, anti-viral, and anti-parasitic therapeutics approved by the FDA since 2005 as well as compounds in clinical development that are natural products or are bioinspired. The chapter also describes new technologies that can accelerate the future discovery of natural anti-infectives.

Antimicrobial resistance is a type of drug resistance where a microorganism is able to survive exposure to the antimicrobial agent. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a horizontal fashion by conjugation, transduction or transformation. Resistance can be intrinsic as a naturally occurring trait arising from the biology of the organism, or acquired by mutation or by acquisition of new DNA. Many diseases are increasingly difficult to treat because of the emergence of drug-resistant organisms, including HIV and other viruses; bacteria such as staphylococci, enterococci, and E. coli which cause serious infections in hospitalized patients; bacteria that cause respiratory diseases such as pneumonia and tuberculosis; food-borne pathogens such as Salmonella and Campylobacter; sexually transmitted organisms such as Neisseria gonorrhoeae; Candida and other fungi; and parasites such as Plasmodium falciparum, the cause of malaria. The emergence of antimicrobial resistance is not a new or unexpected phenomenon. It is an inevitable result of the rapid replication and evolution of microbes. The main mechanisms by which microorganisms exhibit resistance to antimicrobials are: drug inactivation or modification, alteration of target site, alteration of metabolic pathway, and reduced drug accumulation by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface. Additionally, increased mutation rate as a stress response can occur. Factors contributing towards resistance include overuse of broad-spectrum antibiotics, incorrect diagnosis, unnecessary prescriptions, and improper use of antibiotics by patients. The molecular mechanisms of drug resistance provide the essential knowledge on new drug development and clinical use. These mechanisms include enzyme catalyzed antibiotic modifications, bypass of antibiotic targets and active efflux of drugs from the cell. Multidrug resistance can be reversed by a variety of pharmacological agents which promote drug accumulation. Monoclonal antibodies provide a potentially valuable alternative means of reversing multidrug resistance. Understanding the chemical rationale and underpinnings of resistance is an essential component of our response to this clinical challenge.

Malaria is an infectious disease endemic to 106 countries of the tropical and subtropical regions of the world. According to the World Health Organization there were 216 million cases of malaria in 2010 that resulted in 655000 deaths. Children under the age of 5 are the most vulnerable, but approximately half of the world’s population is at risk. Malaria is a febrile illness caused by parasitic protozoa of the genus Plasmodium, and transmitted exclusively by Anopheles mosquitoes. Control involves both prevention, through the use of indoor insecticide spraying with pyrethroids, insecticide treated bed nets, drug treatment of populations at high risk of infection and disease treatment. Malaria can be cured, but the development of resistance by Plasmodium is recurrent. Due to its high mortality and morbidity, the eradication of this disease has high priority in the UN 2000 Millennium Development Goals. As a result of renewed efforts, malaria related mortality decreased by 26% in the period 2000-2010, but control tools are limited. Presently there are no vaccines registered for this disease. The most deadly variant, caused by Plasmodium falciparum, is treated with artemisinin-based combination therapy with a 4-aminoquinoline or an amino alcohol. Recent reports of mosquito resistance to pyrethroid insecticides and of Plasmodium to artemisinin are serious causes for concern. The development of novel drugs remains a big challenge. This chapter highlights the state-of-the-art in malaria prevention and treatment. The literature published since 2000 on the development of new leads for chemotherapy is also reviewed.