Frontiers in Clinical Drug Research: Anti-Infectives

Genome mining consists in assessing the potential encoded in the genome of microorganisms to produce novel secondary metabolites. Actinobacteria have been reported to hold unexplored potential for the biosynthesis of secondary metabolites, according to the number of gene clusters predicted from recently published genome sequences. This is of significant interest in the area of anti-infectives, since many of the secondary metabolites produced by Actinobacteria have been reported to have antibacterial, antiviral and antitumor properties. The first part of this review offers an overview on in silico bioinformatics software and databases for the prediction of gene clusters involved in the production of putative secondary metabolites. The second part of this review encompasses experimental metabolomics techniques, facilitated by mass spectrometry and quantitative proteomics, all of which have the end goal to identify and characterize secondary metabolites. Examples where metabolomics were associated with computational prediction tools to propose the link between genes and metabolites have been highlighted. As an addition, this review also explores the potential of the OSMAC and co-culturing experimental approaches to induce the expression of silent gene clusters under laboratory conditions. Examples are offered of novel secondary metabolites and gene clusters discovered following a genome mining approach.

AIDS is a challenge to mankind. Widespread use of cART changed HIV from a progressive illness with a lethal prognosis into a chronic controlled disease with some side-effects. There is a problem of latent infection or viral reservoir(s), which is unaffected by ART and is not recognized by the immune system. Many researches have concentrated on reducing/disrupting the latent viral reservoir(s) to get rid of HIV. Mucosal surfaces are the entry point and the major regions of HIV-replication. HIV is associated with dramatic loss of gastrointestinal Th17 cells, high mucosal permeability, and chronic inflammation. Effective treatments or prophylaxis at the mucosal level are much needed. Understanding the interplay between microbiota and HIV is important for development successful strategies for HIV/AIDS prevention, treatment and care. Increasing evidence indicate that microbiota can play an important role in HIV transmission and pathogenesis. A new powerful probiotic product (PP) was developed. PP stimulates growth of symbiotic microflora and has a very broad spectrum of antimicrobial activity. PP boosts the immune system. The strongest stimulation of mucosal immune system occurred when PP was administered directly at a mucosal surface. Various routes of PP administration are discussed. PP can improve function of cardiovascular system and cognitive function in HIV/AIDS patients. PP provided relief from opportunistic infections and improved immunological status in HIV/AIDS individuals. It is expected that PP can be used as supplemental therapy to cART.

With effective antiretroviral treatment available for patients, acquired immunodeficiency syndrome (AIDS) is currently considered as a chronic disease. The life expectancy for HIV/AIDS patients on combined antiretroviral treatment (cART) is close to hundred percent with less pain. Such achievement was a dream for scientists and patients during the past twenty five years. The subsequent stage is the complete eradication of the human immunodeficiency virus (HIV) and a cure for AIDS. However, due to the HIV strategic ability of being able to hide in silence as a “provirus” inside its target cells for years, its high rate of mutations and its ability to change its outer envelope with the advantage of staying one step ahead of the immune responses, scientists used to believe that it is almost impossible to eradicate HIV from the human body. The hope for a “sterilizing cure” so that all traces of HIV are eliminated from the body, and/or a “functional cure” so that HIV is controlled by the function of the immune system, is not a dream anymore. Recently, with the discovery of cancer drugs, such as vorinostat, scientists believe that a cure for AIDS is possible with the complete eradication of HIV from the human body. With the advanced knowledge about HIV and the immune responses to it, hopes and optimism for an HIV/AIDS-cure is a hot topic now and we can dream that soon we will be living in an HIV/AIDS free world. There are currently more than 25 anti-HIV drugs used for the treatment of HIV/AIDS patients. This chapter briefly describes our knowledge of the anti-HIV agents currently available and the future plans for designing more effective agents against HIV in its state as a hidden provirus and as a released virus. The chapter will also discuss the way forward for the complete eradication of HIV.

Higher plants produce secondary metabolites involved in defense mechanisms against herbivores, pests and pathogens. These phytochemicals have also potential healthy properties on human organism, including antioxidant, antiinflammatory and anti-microbial. The pressure to discover and develop new and effective anti-infectious substances has grown due to the intensification of new and reemerging infectious diseases as well as the increasing resistance to the antibiotics in current clinical use. There are several approaches to control diseases caused by microorganisms, and one of them is the use of natural bioactive chemicals that can combat the infection. The essential oils, polyphenols and glycosidic glucosinolates extracted from various species (e.g. medicinal and aromatic plants) have shown promising anti-microbial activity against several pathogens responsible for human diseases. Some of these diseases include mouth diseases as periodontitis, urinary infections, acne, stomach cancer and ulcers associated with Helicobacter pylori, wound infections and gastric infections. Beyond the in vitro and in vivo studies, several compounds from the plant secondary metabolites have been subjected to clinical trials in order to validate their efficacy as anti-infectives (e.g. proanthocyanidins, a polyphenol, that have been tested against periodontitis or tea tree oil 4% against methicillin-resistant Staphylococcus aureus – MRSA) for future prescription. As most of these compounds have poor water solubility and are easily oxidized a chemical transformation which may alter their anti-infective properties, new strategies are being considered both to protect these phytochemicals against oxidation and to enhance their bioavailability and delivery to the desired organs. This chapter summarizes and discuss the most promising phytochemicals that are being used to treat human diseases, antimicrobial mechanisms, the results of clinical trials and the new approaches based on nanoencapsulation strategies to deliver and target these compounds in vivo.

Increasing antibiotic resistant pathogens incidence brings to an end of “the antibiotic era” which extended over the past 50 years, and necessitates exploration of alternative approaches to combat emerging infections. Increase global spread of drug resistance pathogens has prompted researchers to search for new strategies for microbial eradication. The efficient and often selective inactivation of microbial pathogens by means of photosensitized processes (Photodynamic therapy) has opened favourable avenues to treat numerable infectious diseases. Antimicrobial Photodynamic therapy (APDT) is a light-based antimicrobial therapy capable of efficiently eradicating wide microorganisms. It is an oxygen-dependent photochemical reaction that occurs upon light mediated activation of a photosensitizing compound leading to the generation of reactive oxygen species. Antimicrobial photodynamic therapy is a topical, non-invasive approach suitable for treating local infections. This chapter focus on introduction to antimicrobial photodynamic therapy with an emphasis on the use of photodynamic therapy for the treatment of resistant microbial strains.