Frontiers in Anti-Infective Drug Discovery

Recent developments about physics of diffusion for the infection pathway of virus in cytoplasm of a living cell are reported. Specifically, the following three issues are discussed based on the experimental fact that the exponent of anomalous diffusion of the virus fluctuates depending on localized areas of the cytoplasm. Firstly, a theoretical framework developed in view of superstatistics offers a generalized fractional kinetics for describing the infection pathway of the virus over the cytoplasm. There, traditional theory of anomalous diffusion is generalized by introducing exponent fluctuations. Then, the framework explicitly takes into account the existence of two largely separated time scales in the infection pathway. Secondly, a statistical distribution of the fluctuations proposed from the experimental data can be derived by the maximum entropy principle. Thirdly, the motion of the virus over the cytoplasm may obey a scaling law. Consequently, a kinetic theory for the infection pathway of the virus in the cytoplasm is established.

The use of medicinal plants probably dates back thousands of years. There is archaeological evidence that dates back to their first use, probably to 60,000 years ago. The main products of the plants, which have shown antimicrobial activity, can be classified as phenolics, terpenoids, essential oils (EOs), alkaloids, lectins, polypeptides, and polyacetilenes. Among plant extracts, the essential oils have been used in traditional medicine as therapeutic remedies in the past thanks to their pharmacological properties and their therapeutic importance has been discussed on numerous occasions in the literature. According to the literature, it is known that some EOs possess good antimicrobial activity even against multi-drug resistant (MDR) strains and it has also been seen that some EOs can improve the activity of antibiotics, reducing the dose and toxicity, when used in combination. This review will discuss the antimicrobial activity of EOs with particular attention on their components that can have biological applications, and attention will be focused on those EOs that have shown an activity against MDR microorganisms.

Studies on bioactive proteins and peptides, as well as their potential applications, have continuously increased over the last 20 years. They can be found in all living organisms, from prokaryotes to eukaryotes, and have been detected in different food matrices, maybe the most useful and reliable sources of these molecules. These proteins are referred to as bioactive compounds since they can modify several cellular bioprocesses in order to improve human health human health. Bioactive molecules can occur naturally or can be released from a principal protein after chemical or enzymatic hydrolysis or food fermentation. Bioactive peptides and proteins derived from food matrices or released from microorganisms can present intrinsic antihypertensive, hormone-like, antimicrobial, anti-cancer or antioxidant activities. There is a large demand for natural preservatives and for minimally processed food, researchers have intensified the search for bioactive peptides and proteins, especially those with antimicrobial properties, which are powerful substitutes for conventional food preservatives. This chapter describes the features of antimicrobial peptides and their combination to polymeric materials for food preservation by preventing microorganism proliferation. For this purpose, the bioactive molecules are complexed to chitosan bioactive molecules with chitosan biofilms, creating an antimicrobial packaging. Despite the changes that can occur in the physical properties of these biofilms, the incorporation of antimicrobial peptides to bioplastic biofilms could guarantee the quality and safety of foodstuffs, contributing in extending their shelf life.

Multidrug resistant pathogenic bacteria pose a serious public health concern as their recalcitrant nature enhances treatment failure of infectious diseases. Several molecular mechanisms are responsible for multidrug resistance in bacteria. A major antibacterial resistance mechanism involves active drug efflux, grouped into transporter superfamilies. Of these, the major facilitator superfamily harbors clinically important drug and multidrug efflux pumps and constitutes a large number of transporters that share similarities in protein sequences, three-dimensional protein structures, energy modes, and evolutionary origin. Multidrug efflux pumps of the major facilitator superfamily in bacterial pathogens compromise the efficacy of infectious disease treatments. Thus, inhibition of these antibacterial efflux pumps is critical in order to circumvent drug resistance and potentially restore the clinical utility of infectious disease chemotherapy. This chapter summarizes bacterial resistance systems and multidrug efflux pumps from the major facilitator superfamily and the nature of efflux pump inhibitors.

Mastitis is considered worldwide as the disease of cattle that causes severe economic losses in dairy industry worldwide and is usually associated with the presence of infectious agents as bacteria. Bacterial pathogens have been classified in contagious, environmental and opportunistic pathogens. Antibiotic therapy is one of the routine treatments for mastitis. However, antibiotics are moderately effective and their indiscriminate use leads to resistant strains. In addition, residues remain in milk with implications for human health.

Therefore, one of the objectives of the dairy industry is to reduce the use of antibiotics in animals food producing. The mammary gland has defense mechanisms against invading pathogens.

The incidence of mastitis increases when these mechanisms are impaired. Polymorphonuclear neutrophils (PMN), macrophages and lymphocytes play a very important role in the defense against mastitis. These cells regulate both the innate and adaptive response. Alternative therapies are conducted in order to both reinforce the antimicrobial therapy and to increase the natural defenses of the mammary gland. The application of immunomodulatory compounds to stimulate the immune response of the mammary gland is one of the most innovative alternative strategies studied today.

In this context, immunomodulators compounds derived from medicinal plants appear as an effective alternative therapy. Several studies have reported that ginseng saponins or ginsenosides of Panax ginseng, extracts of Tinospora cordifolia or Taraxacum mongolicum, flavonoids of Rosa agrestis among others, have stimulatory effects on immune response of the mammary gland with potential use in the treatment of bovine mastitis. Strategies to enhance the immune response of the udder will heavily impact the animals’ ability to resist pathogen infection.

It is being realized that most of the pathogens responsible for causing diseases in human and other animals have become resistant to general antibiotics. Therefore, there is more emphasis on the development of specific drugs in present day researches. Bioinformatics has played an important role in this field and due to which cost of drug development is curtailed even upto 60 to 70%. During work on specific drug development, important part is determination of drug target(s). A drug target is a biological molecule whose activity is altered by drug that results in desirable therapeutic effect. Drug targets are mainly enzymes, receptors, ion channels or nucleic acids. Identification of drug targets is very complex process during early drug discovery. After genome sequencing, bioinformatics design essential tools are used for in silico drug target identification. These include tools for genome/ proteome analysis, similarity searching, EST identification, structure prediction, functional prediction, localization prediction, pattern matching, pathway mapping, network analysis, proteinprotein interaction and many more. Using combination of these tools, different approaches are designed to find the drug targets. In this chapter, we have tried to describe some of these approaches with the tools that are used for identification of drug targets. In addition, we also discussed the results obtained in many cases by applying these approaches.

Today, drug discovery is relying on computational methods to accelerate the identification of potential drug targets. This acceleration leads to fast drug discovery process. These computational methods are used based on the available data and resources of the pathogen and disease. However combinations of approaches are also used to fully characterize the drug target. Once a drug target is identified, it is validated by several wet lab techniques.