Frontiers in Clinical Drug Research: Anti-Infectives

Bacterial and viral infections are still a major threat of human health. The increasing resistance of bacterial isolates to common antibiotics and the lack of new compounds reaching the clinic leading to serious problems in health care. The variability of different virus families with individual entry pathways and replication strategies make the development of suitable therapeutics with cross-species activity complicated. Furthermore, the infections often cause each other, so that an initial virus infection is frequently accompanied by a bacterial ‘superinfection’ with severe consequences.

We developed a new class of compounds based on polypeptides, which exhibit broadspectrum antiviral activity with simultaneous inhibition of important bacterial pathogenicity factors such as lipopolysaccharide (LPS, endotoxin) and lipoproteins. Here, we summarise recent results and discuss them in the context of the progress made in the field of polypeptides as novel anti-infective therapeutic agents.

Antimicrobial agents are used to treat infections involving biological agents (pathogens) other than humans and the goal is to rid the host of the pathogen. Because of the involvement of a second living agent in the Host-Pathogen-Antimicrobial agent triangle, drug therapy is affected by the biological characteristics of the pathogen including its tissue specificity and most importantly the changes it undergoes to survive while being exposed to the antimicrobial agent. It has become very clear that the drugs that are used to treat infections allow the pathogens to enhance their capability to become resistant and furthermore transfer this resistance to other pathogens. Only appropriate and judicious use of anti-infectives can prolong their effectiveness.

This chapter will provide an overview of the historical perspective and current antimicrobial agents. This will be followed by a discussion on the recently developed antimicrobial agents, those that are in development, including those with novel mechanisms of action.

Human pathogenic bacteria and viruses are significant etiology of different types of infectious diseases that cause extremely high morbidity and mortality worldwide. Continuous failure of anti- pathogen/infective agents and therapies, as well as the paucity of postexposure therapeutics greatly facilitates the emergence and dissemination of pathogenic bacterial isolates and virus phenotypes with multi-drug resistance (MDR) or pan-drug resistance (PDR). Additionally, the potential use of these bacteria and viruses in acts of bioterrorism poses tremendous threat to global security. Novel counterstrike strategy of using single-stranded antisense oligonucleotides (ASOs) as prospective gene silencers has been a major area of anti-infective study, leading a potential revolution in the development of antibacterial and antiviral therapeutics by addressing the targets that are “undruggable” for traditional pharmaceutical approaches. Given 30 years of technology advances in elucidation of antisense mechanism, characterization of ASOs chemical modification, and refinement of delivery systems, ASOs based anti-infective strategy displays advantageous features of conceptual simplicity, straightforward designing and quick drug identification methods. The stericblocking ASOs offer improving sequence-specific anti-infective effects in vitro and in animal models of fatal infections, which enables themselves candidates for pre-clinical and clinical tests. This chapter puts together and discusses the important advances in the field based on the above mentioned technologies and the latest development of potential targets and therapeutic AS-ODNs that have reached clinical trials with antibacterial or antiviral protocols.

Flavivirus become a re-emerging problem to humans and animals. Through the availability of efficient whole inactivated viral vaccines against Yellow Fever (YF), Japanese Encephalitis (JEV), the burden of these two diseases has been minimized to some extent. Restrictions in the use of these vaccines, accessibility and cost for these usage in places where the disease is endemic and failures in attempt to produce vaccines against Dengue virus (DENV), West Nile virus (WNV), has prompted to go for other effective anti-viral strategies. Incomplete understanding in the host immune mechanism, lack of suitable animal models is the main reasons for the unavailability of an effective antiviral treatment. Hence supportive measures and symptomatic treatment are the only available choice. In this chapter, the major vaccines currently available against flavivirus and new approaches utilized for designing novel vaccine candidates and antiviral agents targeting various pathways in the flavivirus life-cycle are discussed.

Defining the molecular basis of the infectious diseases by the highly accumulated data on genetics and molecular biology facilitated developing new prophylactic and therapeutic vaccination strategies against human and animal diseases. On the other hand, vaccine development process still has many technical and economical limitations. Therefore, low-income countries, which do not have powerful healthcare infrastructure, neither produce their own vaccines nor benefit enough from the current vaccination programs. In this aspect, plants are promising to be used as biofactories for producing edible vaccines and several therapeutics due to their easy manipulations and also low-cost manufacturing properties. In this chapter, the advantages, limitations of the edible vaccines, the studies related to plant-derived edible vaccines and therapeutics up to date are summarized.

In the 20th century, particularly in the 1950s and 1960s, the discovery and development of antimicrobial agents along with stringent vaccination schedule and improved hygiene led to tremendous improvements in life expectancy globally. However, in the last 20 years, it is distressing to observe that bacterial resistance has emerged as a major threat and some authorities are warning about a return to the preantibiotic era, where even trivial infections could prove life threatening. In developing countries, neglected diseases kill more than half a million people annually, and inflict severe economic, psychological and physical damage in much larger populations. In the last decade, advances in our understanding of molecular physiology and genomics of these pathogens along with significant advances in Medicinal Chemistry (e.g., computer–aided drug design) and Biotechnology have ushered an exciting era of new drug discovery research. For a long time, the major pharmaceutical companies focused their attention towards discovering new drugs primarily against Gram-positive pathogens, and recently there appears to be renewed research and development efforts focused on multidrug resistant Gram-negative pathogens. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are responsible for multidrug resistant nosocomial infections and resistance of these clinical isolates to antimicrobial agents presents serious therapeutic dilemmas for physicians. Infectious diseases can be difficult to diagnose, the causative agent may not be clinically apparent and untreated infections can have dire consequences. Latest strategies to prevent the emergence and spread of antimicrobial resistance and to “re-engineer” the effective life of available drugs are urgently required. Medical practitioners and researchers should optimize clinical outcomes while minimizing unintended consequences of antimicrobial use, including toxicity, selection of pathogenic organisms and emergence of resistance. Given the association between antimicrobial use and the selection of resistance pathogens, the frequency of inappropriate use of antimicrobials is often used as a surrogate marker for the avoidable impact of antibiotic resistance. This review will outline recent progress made globally in the discovery and development of new drugs against Gram-negative pathogens.

Bacterial enteric pathogens are by far the most dominant scourge of mankind. There are more than 200 million cases and 3 million deaths caused by these bacteria every year. Before the antimicrobial era, there were pandemics of enteric diseases which sometimes swept away whole populations. Advent of antimicrobial era provided a tool in the hand of mankind to fight this menace. In the beginning the results were promising and there was optimism of a decisive victory against disease causing bacteria. But the reality dawned within a couple of decades when antimicrobial resistance started to emerge and every new antimicrobial was generally knocked out in a couple of years. It became apparent that these bacteria held a distinct advantage because of very fast evolution rate due to relatively simple and small genome and short generation time. Currently, we are always playing a catch up game because the enemy is always ahead. The emergence of multiple drug resistance (MDR) has aggravated the situation and there is a distinct possibility that some of these menacing bugs may get out of control and situation of pre-antimicrobial era may return. Recently, a new term extreme-drug resistance (XDR) has been coined. This refers to bacteria resistant to all available drugs. This aptly summarizes the situation we are facing today. This catastrophe can only be avoided by putting more efforts in developing new concepts and products. This chapter is an effort to encompass the properties of these pathogens, the antimicrobials currently in use and the mechanisms of drug resistance evolved by these formidable bacteria.

Almost two million Americans per year develop hospital-acquired infections, resulting in 99,000 deaths, the vast majority of which are due to antibiotic-resistant pathogens. Because of the pressing public concern over the emergence and global spread of MDR Gram-positive bacteria, as well as the serious and life threatening nature of these diseases and the limitations of current available antibiotics, global efforts are now focused on the development of novel and alternative antibacterial. One very promising new class of antimicrobial agents includes members of a widespread family of bacteriophage-encoded, bacterial cell wall-hydrolytic enzymes, or lysins. Lysins represent a new class of antibacterial agents against Gram-positive bacteria including multidrug-resistant bacteria, with a mechanism of action distinct from antibiotics. In this review, we will describe the nature of phage lysins, how they are distinguished from antibiotics, and how they may be applied to human medicine. Finally, we will discuss the hurdles to developing a new antimicrobial class and bringing it from the lab bench to the market.