Frontiers in Anti-Infective Drug Discovery

The term “Gastro-Intestinal (GI) cancer” indicates a group of tumors that affect the digestive system. Despite progress in treatment, these widespread types of malignant condition represent a serious health problem in the world. GI cancer is a multi-factorial and multi-stage involved disorder, its progression is influenced by environmental and genetic elements and the involvement of microbial population has also recently been recognized in many studies. Today, Next Generation Sequencing (NGS) approach has been used to elucidate the involvement of microorganisms in initiating and facilitating the process of GI cancer. In this chapter, we would like to clarify the role played by the gastrointestinal microflora in the genesis of GI cancers. This chapter will draw the state of the art in the study of the GI microbiota and how the dysbiosis could affect oncogenesis, tumor progression and response to cancer.

Dengue virus (DENV), a member of the genus Flavivirus in the family Flaviviridae, is the causative agent of the major human viral infection transmitted by mosquitoes in the world with about 390 million annual infections. Recently, a tetravalent vaccine has been licensed for use in highly endemic countries but protective efficacy is not complete and equivalent against the four DENV serotypes. Specific therapeutics is not available at present and treatment is limited to symptomatic supportive care. The reliance of DENV on several host processes and molecules for productive infection highlights the targeting of a cellular factor as an attractive antiviral approach. Since many host requirements are shared by different pathogenic flaviviruses, like Zika virus, West Nile virus, yellow fever virus, Japanese encephalitis virus, tick-borne encephalitis virus, this strategy may provide a wide range effective inhibitory agent and also reduce the possible emergence of antiviral resistant variants. In fact, the few drugs just evaluated or in evaluation at this moment in clinical trials include the host cell-directed compounds chloroquine, lovastatin, prednisolone and celgosivir. This review focuses on the antiviral potential of host cell factors directly participating in the viral cycle of infection as well as those ones involved in the innate antiviral response triggered to restrict and control viral dissemination and pathogenesis.

The emergence of multi-drug resistant pathogenic bacteria, coupled with a decline in discovery of new drugs, has gradually steered the world to the doorstep of post-antibiotic era as trivial infections often become untreatable with the existing antibiotics. Therefore, design and development of new therapeutic strategies would be of paramount importance, primarily by interfering with mechanisms leading to drug resistance. Accordingly, researchers are aiming at the restoration of activity of existing antibiotics by using resistance modifying agents (RMA), and looking for suitable secondary plant metabolites to function as RMAs. Plant-derived RMAs are believed to rejuvenate the action of conventional antibiotics via unique mechanisms, as for example, by acting upon bacterial efflux pumps, enhancing membrane permeability, and inhibiting the synthesis of proteins responsible for bacterial resistance. However, due to the lack of adequate pharmacological data, these phytochemicals are yet to be approved for clinical use, despite the upcoming prospect of their therapeutic application. This chapter focuses on the relevant screening strategies to characterise new RMAs from plant constituents exhibiting resistance modifying activity against pathogenic bacteria. Also, the respective mode of synergistic interaction of these agents has been discussed in view of their potential application to supplement the conventional antibiotics against drug-resistant bacterial infections.

Projects on design and discovery of antibacterial compounds are at present one of the main research lines in academia and to the lesser extent in pharmaceutical industry. Application of computer-aided drug design (CADD) techniques to drug discovery approaches may lead to a reduction of up to 50% in the cost of drug design. Effective drug design is facilitated when the 3D structure of a drug target is known from experimental or molecular modeling studies (e.g. from homology modelling). Nowadays, diverse techniques of molecular docking and molecular dynamics (MD) constitute important computational tools to study drug-protein interactions at the molecular level. Ligand-based and receptor-based methods of virtual screening are becoming more and more powerful for identification of potential hits. It should be stressed, however, that the main issue with target-based automated HTS approaches as well as virtual screening methods is the fact that identified substances although active on the target, are frequently ineffective in the host. In this chapter we present successes and challenges of molecular modelling techniques as applied to antibacterial drugs. The covered techniques are: homology modeling, molecular docking (including virtual screening), molecular dynamics, quantitative structure-activity relationship (QSAR), pharmacophore models. In spite of the successes, there are specific problems and challenges connected with application of CADD to antibacterial drug discovery. CADD techniques enable to design the compound active on a given target, often without considerations if a molecule is able to reach the target. It is thus needed to develop rules for effective bacterial penetration to be used for filtering compound libraries instead of Lipinski’s filters. Next, CADD methods are capable to address only partially the problem of antibiotic resistance. However, progress in in silico pharmacology and toxicology allows to design safer molecules which is important for antibacterial drugs used in relatively high concentrations.In summary, the importance of CADD techniques in academia and industry for discovery of novel antibacterial compounds cannot be overestimated. Although experimental verification of computational results is still required, these methods limit significantly the number of necessary experiments.

Aptamers are single-stranded DNA or RNA molecules, which can bind their targets with high affinity and specificity. SELEX (Systematic Evolution of Ligands by Exponential Enrichment) is the technology that allows to select aptamers from a random oligonucleotide library. Binding properties of aptamers are comparable to those of antibodies. But, unlike antibodies, aptamer production is a more rapid and less expensive process. One remarkable application is aptamer-based biosensors for specific and sensitive detection of bacterial toxins. In addition, a few aptamers have been shown to inhibit pathogens by blocking the activity of virulence factors. The chapter mainly covers aptamers that target virulence factors, rather than pathogen cells. First, general methodology for selection of aptamers is described. Then, aptamers developed against toxins, protein virulence factors and quorum sensing molecules are reviewed. In addition, chemical modification strategies to improve drug potential of aptamers are addressed. Although aptamers are excellent antimicrobial drug candidates, there are only a few studies that describe functional cell-based assays and potential therapeutic use. In this chapter, analytical applications of aptamers, as well as limited studies on their antimicrobial effect are reviewed.

Since ages, fungal pathogens are exploiting the human host by causing superficial to deep-seated fungal infections. Candida albicans, being the most prevalent pathogen, accounts for approximately 50–60% or more causes of candidiasis in humans leading to alarming mortality worldwide. In spite of significant advances being made in the improvement of antifungal drugs, only limited number of antifungal drugs are currently available and that too are not able to keep pace with the evolution and development of multidrug resistance (MDR) in C. albicans. Among the several causes of MDR, overexpression of drug efflux pumps contributes majorly to MDR. Thus, blocking or modulating the function of the drug efflux pumps still represents an attractive approach to combat MDR. The natural sources have the plethora of many promising natural compounds which can efficiently be exploited to improve the antifungal therapeutics. There is a need to unravel the intrinsic studies on natural inhibitors of efflux pumps. This book chapter unfolds the role of such natural compounds that target drug efflux pumps (the major culprits of MDR) thereby having the potential to chemosensitize towards known antifungal drugs.

There is a growing interest in “medical gases” for their role in infection. Hydrogen sulfide (H2S) is a physiological gaseous mediator that has been recognized as an important signalling molecule to regulate infections. The role of H2S in different infections such as viruses (paramyxoviruses), bacteria (Mycobacterium tuberculosis), mycoplasma (Mycoplasma fermentans) and fungi (Aspergillus niger) as well as in conditions like sepsis and malaria and in antibiotic resistance is being actively investigated because of its therapeutic potential. As we do not have definitive therapeutic agents such as antimicrobials or vaccines against many pathogenic agents, the immuno-regulatory and microbial properties of H2S make it an ideal candidate for the treatment of infectious diseases. Therefore, understanding the mechanisms underlying H2S-mediated regulation of different infectious diseases would help in developing H2S-based drugs as therapeutic molecules. A description of recent understanding of H2S role in different infections is presented in this chapter.