Frontiers in Anti-Infective Drug Discovery

Background: The main recommended regimens to eradicate Helicobacter pylori infection fail in ≥20% of the cases. Several substitutes for triple therapies have been proposed, and non-bismuth quadruple therapy is one of the most widely used.

Aim: To systematically review the efficacy of non-bismuth quadruple regimen (proton pump inhibitor, clarithromycin, amoxicillin and a nitroimidazole) in the eradication of H. pylori infection.

Methods: Bibliographical searches were performed in MEDLINE/EMBASE and relevant congresses. We pooled studies evaluating the concomitant regimen, and of the randomized controlled trials comparing concomitant vs. standard triple therapy, and concomitant vs. sequential therapy.

Results: Fifty-five studies were included (6,906 patients). The meta-analysis showed that concomitant regimen offers an overall eradication rate of 87%. A sub-analysis of studies comparing one-to-one concomitant and triple therapies showed an odds ratio of 2.14 (95% CI=1.51-3.04) towards higher efficacy with concomitant regimen. This figure increased up to 2.41 (95% CI=1.80-3.24; 85% vs. 72%) when comparing arms lasting the same number of days. We also sub-analyzed the comparative efficacy between non-bismuth quadruple concomitant and sequential treatments, and concomitant achieved an odds ratio of 1.49 (95% CI=1.21-1.85) towards higher eradication results than sequential regimen.

Conclusions: Non-bismuth quadruple (concomitant) therapy achieves high efficacy in H. pylori eradication, superior to standard triple and sequential therapy. Concomitant may be more appropriate than sequential therapy for patients with clarithromycin and/or metronidazole resistance. Higher acid suppression and/or longer duration are optimizations that can increase even more its efficacy.

After the discovery of the infectious bronchitis virus (IBV) in 1932, Coronaviridae emerged as a family of viruses constituted of a positive-sense singlestranded RNA ((+)ssRNA) genome. Recently, the Coronavirus disease-2019 (COVID- 19), which is caused by a new virus called SARS-CoV-2 (provisionally titled 2019- nCoV), was declared pandemic since it reached global levels of infection. In comparison, this disease spread globally more quickly than previously reported SARS and MERS-CoV outbreaks. The impacts on global health systems (as well as the world economy, estimated to cost US$ 1 trillion) highlighted the urgent need to search for efficient pharmacotherapy targeting potential macromolecules from SARS-CoV-2 since there are no licensed vaccines or approved drugs until today. In this chapter, we will demonstrate all strategies that have been used to discover and design bioactive molecules against this viral infection, compiling from classical to computer-aided drug design, including also the drug repurposing. This last, it is based on analogs produced for past outbreaks related to SARS- and MERS-CoV. Finally, we aim to provide valuable information that could be applied for designing new safe, low cost, and selective lead-compounds against these emerging viruses.

In recent years, the discovery of new and effective antibiotics has slowed dramatically due to the rapid and widespread development of bacterial drug resistance and many pharmaceutical companies exiting the field. Reliance on conventional drug discovery methods, while effective in the past, has led to significant present-day challenges that are becoming increasingly difficult to overcome. A fundamental challenge to the development of new antibiotics against multi-drug resistant bacteria is the high cost of development relative to expected revenues. Fragment-based drug design (FBDD), which involves screening low molecular weight ligands, can help to drastically reduce the cost of finding initial hits compared with traditional highthroughput screening (HTS). In addition, a knowledge-driven and multi-pronged approach to the subsequent expansion of amenable fragments into high-affinity inhibitors may assist with overcoming hurdles in the hit-to-lead (H2L) optimisation process. Favourable pharmacological and physicochemical properties, as well as strategies against the development of resistance, can be incorporated as part of the fragment expansion process. This chapter discusses the features of the FBDD approach that are relevant and beneficial for antibiotic development. Successful examples and barriers to progress from hit discovery to H2L development, as well as patents, are presented. Finally, the outlook for FBDD in the field of antibiotic development, including the latest FBDD advances and challenges, is discussed.

It is estimated that only in USA, foodborne pathogens cause 48 million illnesses, with 128,000 hospitalizations and 3,000 deaths each year. The growing global emergence of multi-drug-resistant infections raises the need to find alternative methods for the effective treatment of infectious illnesses. Phages possess properties that make them interesting but challenging candidates for different applications, including phage therapy against foodborne bacteria. The results of different clinical studies confirm the safety and efficiency of the use of bacteriophages for this purpose. Bacteriophage applications include water and food safety, agriculture and animal health. There are already several products available in the market. Studies indicate that phages have potent immunomodulatory and anti-inflammatory properties, and are recognized as an important part of the immune system. The use of bacteriophages for the control of foodborne infections should lead to promising alternative therapy. This review focuses on the application of bacteriophages as an antimicrobial alternative for therapies against antibiotic-resistant bacterial infections.

Pathogenic bacteria are evolving at a much faster rate and have the ability to acquire new antibacterial resistance patterns. The most common pathogenic bacteria are now becoming increasingly resistant to available antibiotics. The CDC has suggested to find alternative therapeutics to combat the growing antimicrobial resistance. Thanks to technological development in sequencing platforms and sophisticated bioinformatics pipelines, it now easier to analyze large-scale genomic data and propose alternative and novel treatment options. Subtractive genomics is one such approach that mines whole genomic DNA for identification of potential drug target(s). This strategy employs various computational filters using databases and online servers to screen and prioritize certain candidate proteins. Each filter analyzes the whole proteome of bacteria under study in a step-wise manner. Initially, strainspecific paralogous and host-specific homologous sequences are subtracted from the bacterial proteome to remove duplicates and prevent cytotoxicity and autoimmunity related challenges. The sorted proteome is further refined to identify essential genes involved in crucial metabolic pathways of the pathogen and thus can be used as targets for treatment interventions. Functional annotation is carried out to elucidate the involvement of these proteins in important cellular processes, metabolic pathway, and subcellular location analyses are carried out for finding the probable cellular location of the candidate proteins in the cell. Proteins with certain physicochemical properties like favorable molecular weight, hydrophobicity, and pI are rendered fine drug targets, thus filter. Importantly, the scrutinized proteins are screened against FDA approved DrugBank to identify their druggability potential. Finally, molecular docking analyses of the novel druggable targets with already present drugs are carried out. Only then, the prioritized candidate proteins can prove to be promising candidates for novel drug design and development.

Natural products obtained from the microbes have been reported as substitutes to contemporary drugs obtained from plants. With the increasing need for new therapies, new natural products are being explored using the traditional methods. As only a small fraction of microbes can be cultured in the laboratory, many microbes continue to remain unexplored for their ability to synthesize secondary metabolites. In the past few decades, the reduced cost of DNA sequencing and developments in computational tools have made the Metagenomic Approach effective and popular. Uncultured microbes can be studied through bioprospecting of the unexplored geographical niches. Moreover, Bioinformatics tools have enabled us to find the gene clusters that, in metagenomics, imply the real potential of finding novel open reading frames (ORFs). Screening of genomes for secondary metabolite-genes like nonribosomal peptide synthases (NRPS) and polyketide synthases (PKS), has resulted in the discovery of new or previously known metabolites. Technological advancement and innovations in the culture-independent approach have allowed us to explore novel chemistries from environmental samples to identify the molecules of therapeutic value. This chapter will discuss the methods for identifying secondary metabolite genes from the genome, and the new approaches for functional metagenomic screening toward the discovery of antimicrobials. Moreover, insights into this approach will be provided to generate opportunities to explore natural products for combating the global demand for novel antibiotics.

Nanotechnology has brought a revolution to the world of science and medicine. With time, the dependency on nanotechnological advancement is increasing. Synthesis of nano-scale modulators is a significant domain of focus that employs crude formulations, retro-synthesized, and pure chemicals, mostly from herbal sources with lesser side effects. However, all these methods suffer from drawbacks and limitations. For an eco-friendly nanoparticle synthesis, green chemistry has evolved with a tangential approach for the synthesis of metals (Au, Ag) and metal oxides (ZnO, CuO, TiO). Green synthesis uses plant extracts (leaves, stem, shoot) and microbes (bacteria, fungi, yeast) as reducing intermediate for the production of nanoparticles.

The advantage of these extracts lies within the phenolic constitutes of aldehydes, ketones, proteins, and other biomolecules that implicate the reduction of the nanoparticles.

These green synthesized nanoparticles have high efficacy ranging from anti-bacterial, anti-fungal, and wide applications in medicine. In this chapter, we discuss the methods of green synthesis, their applications, and prospects. The current chapter will pave the way for future applications and better means for the synthesis of nanoparticles leading into a newer direction with varied recognition in nano-life sciences.

Rapidly emerging drug resistance in all classes of pathogenic microorganisms has become a challenging task and a global health issue in recent years. There are very limited alternative options available to cure infectious diseases, as the rate of rise in drug resistance in infectious agents is higher than the arrival of new antimicrobial drugs. There is a dire need to look for new types of anti-infective agents, besides looking for new antibiotics. One of the promising types of antimicrobial agents is aptamers, synthesized through systematic evolution of ligands by exponential enrichment (SELEX) technique. Aptamers hold a significant promise for the treatment of various infectious diseases in the future. In the recent past, a number of successful attempts have been made to select and apply aptamers for the detection and binding of infectious agents and their products for therapeutic purposes. This chapter presents a basic introduction to aptamers and their application as anti-infective agents.