Frontiers in Clinical Drug Research: Anti-Infectives

Antibiotic resistance occurs through several mechanisms that can coexist simultaneously in the same cell. The main ones include modification of the target, reduced permeability, export by active efflux pumps, sequestration of the drug by tight binding to an endogenous molecule, and enzymatic inactivation of the antibiotic molecule. The development of new antibiotics, a path currently being pursued by several laboratories using different approaches, is an obvious answer to the problem of resistance. However, this solution has not yielded the results one would expect; few new antimicrobials have been generated in the past decades. This article illustrates alternative methodologies that are being explored to produce chemicals that, although not having antimicrobial properties, act as potentiators such that combination therapies including the antibiotic and the adjuvant can overcome resistance. These compounds can achieve the expected outcome by inhibition of expression of resistance traits or interference with the function of components of resistance mechanisms.

In the past two to three decades, many catalytic antibodies hydrolyzing VIP, DNA, RNA, HIVgp41, HIVgp120, Factor VIII, H. pylori urease, hemagglutinin of influenza virus, and amyloid-β have been reported. In recent years, catalytic antibodies are used in the stages of in vitro testing as well as in vivo against influenza, rabies, and AIDS viruses. These recent developments are introduced in this chapter. Currently, antibody drugs have been developed in many countries and companies throughout the world. It is said, this development is in a “frenzy of scientific competition,” which may continue for about the next ten years. Alternatively, catalytic antibodies are far superior to normal antibody drugs, since the former can recognize and catalytically degrade the antigen. A general technology for the development of catalytic antibodies is in the pipeline, and once the technology is developed, it could impact the drug industry as far as the use of catalytic antibodies is concerned. The general trends in developing the antibodies and other parameters that could influence the developmental process are discussed here. Based on these considerations and facts, we will briefly mention the perspectives and world trends in catalytic antibody research.

Arenaviruses, enveloped viruses containing a bisegmented single-stranded RNA genome with ambisense coding strategy, include important hemorrhagic-fevercausing viruses representing a public health threat in endemic areas of Africa and South America. In spite of the danger of pathogenic arenaviruses and their increased emergence in recent years, no specific and safe chemotherapy for these viruses is currently available. This chapter covers recent advances in the development of antiviral strategies to face arenavirus infections. New insights in molecular aspects of virus replication and virus-host interactions have allowed the identification of viral and cellular factors as potential target for antiviral therapy. We will revise the main features of arenavirus biology and the mechanism of antiviral action of different molecules derived from natural sources, chemical synthesis and rational structure-based antiviral drug design. The advantage of targeting viral and cell host factors as complementary approaches for therapy intervention will be discussed. We will particularly discuss the use of novel inhibitory strategies and the main advances in the development of innovative screening platforms.

Throughout history, viral diseases have been a serious threat that has constantly jeopardized the global public health. Although great success has been achieved in developing effective vaccines and antiviral drugs to combating them, new viral pathogens are emerging and the old ones evolve to evade current therapeutic options. Upon encountering a pathogenic virus, the host senses the invasion and triggers complex innate and adaptive immune responses to cope with the infection. Although pro-inflammatory responses are critical for the early control of viral replication, excessive inflammation also causes severe injuries to the tissues, thereby contributing to developing viral immunopathologies. Thus, glucocorticoids have been used due to their potential role in controlling the inflammatory response, but, unfortunately, corticosteroid administration has been shown to have a deleterious effect in various viral infections. Therefore, the clinical outcome of the use of steroids in the context of viral diseases is still controversial. Nevertheless, in the last decades, several natural and synthetic steroids have been reported as antiviral agents. Recent findings have demonstrated multiple physiological roles played by steroids during the course of different viral infections. These results encourage the assessment of novel steroids as antiviral and immunomodulatory entities. In this Chapter, we review the most recent advances on this field, focusing on the opportunities that the understanding of the interplay between viral infections and the steroids of the host might provide for the development of new therapies.

Monoclonal antibodies (mAbs) were firstly described by Köhler and Milstein in 1975, and their potential as powerful therapeutic agents recognized in the following years. Currently, the US Food and Drug Administration (FDA) has already approved 56 monoclonal antibodies for the treatment of several diseases, including cancer (e.g. breast cancer, leukemia and prostate cancer), auto-immune disorders (rheumatoid arthritis and Crohn’s disease), asthma, and cardiovascular and infectious diseases. Despite their advantages and therapeutic potential, the cost of manufacturing these biopharmaceuticals with high quality and purity level is still extremely high due to the absence of current cost-effective extraction/purification methods, and which has also impaired their widespread application as recurrent therapeutic agents. The upstream processing of mAbs has gone through several improvements in recent years, by using alternative expression systems or by optimizing the medium formulations and feeding strategies. On the contrary, the downstream processing is considered the bottleneck in the manufacturing of mAbs for therapeutic purposes at reliable costs, representing up to 80% of their total production costs – which is a frontier in clinical drug research. In the past years, several chromatographic and non-chromatographic alternatives have been explored for this purpose, resulting in the development of efficient platforms for the purification of mAbs, that are overviewed and discussed in this chapter. In summary, this chapter provides a vision on the current state of the art of the biopharmaceuticals market, on the production and use of mAbs as valuable therapeutic agents, including their use for the treatment of infectious diseases, while summarizing the mAbs-based products already approved by regulatory agencies. New insights concerning the development of new and alternative platforms or the extraction and purification of mAbs are also discussed, while envisaging the adoption of the most relevant techniques by the pharmaceutical industry to allow the widespread use of biopharmaceuticals in the near future.

The use of medical indwelling devices (MID) became a hallmark in medicine during the last few decades. While it represents a considerable progress in terms of chances of patient survival, several associated drawbacks demand continuous research in terms of optimization of such devices or of its use in order to cope with complications, which could be life threatening. Notably infection remains one of the most inherent complications associated with MIDs, constituting the most feared threat. Very frequently, it demands MID replacement, often leading to its lost, to prolonged patient hospitalization and, ultimately, to patient death. In any case, it represents a serious burden to healthcare systems in terms of allocated resources and financial costs. The formation of biofilm became the paradigm of MID infection. Independently of the nature of such devices, following its placement or implantation infection remains hard or impossible to control with common antibiotics. In fact, antibiotic drugs hardly penetrate the polymeric matrix of biofilm, which allows organisms to evade its activity. Moreover, organisms in biofilm display increased antibiotic resistance, in comparison to its planktonic counterparts. While diverse preventive strategies have been attempted, with variable success, fewer options remain available once overt infection develops, apart from device removal. Nevertheless novel alternatives have been proposed and recent research efforts with specific devices have provided encouraging results. Our research team has been addressing this problematic from a clinical perspective and, in particular, from a laboratorial point of view, conducting both in vitro and in vivo studies in biofilm infection models. The authors propose to conduct an extensive review and discussion of the literature available concerning biofilm involvement in MID infection, having as main focus the eradication of biofilm at the surface of MID, apart from prevention of the initial steps of its formation. While a large variety of devices will be discussed, like central venous catheters, prosthetic or cardiovascular implants, special consideration will be dedicated to high value devices such as heart pace-makers and cerebral stimulators, attending to the direct high costs associated to its lost following infection.