Frontiers in Anti-Infective Drug Discovery

Despite advances in the treatment of tuberculosis (TB) and increased effort to discover new anti-TB drugs, 8.6 million people were affected by Mycobacterium tuberculosis infection, leading to 1.3 million deaths in 2013. Tuberculosis is a substantial threat to public health because of co-infection with HIV and the emergence of resistant strains (MDR and XDR). The main obstacles for the discovery of new drugs against TB include high cost, lack of investment by large pharmaceutical companies and lack of infrastructure in the countries affected by this disease. The global effort to eliminate tuberculosis includes contributions by the Global Alliance for TB Drug Development (TB Alliance), several research groups, regulatory agencies, and institutions such as the NIH (National Institutes of Health) and Bill and Melinda Gates Foundation. This chapter discusses factors that impede anti-TB drug discovery, which include the development of bacterial drug resistance, role of bacterial efflux pumps, cross-resistance, drug interactions with antiretrovirals and lack of investment by pharmaceutical industries; furthermore, new drugs that are being tested for the treatment of TB are discussed.

The antibiotics are destined for obsolescence as microbes would find a way to deal with them either by innate or by acquired genes. It is truly said that the power of bacteria should never be underestimated. There is a constant race between the humans for design and use of new drugs and the acquisition of genes by bacteria to render these novel drugs harmless. Situation has worsened with the indiscriminate use of antibiotics in human and animal health, agriculture, aquaculture and poultry. There have been reports of extremely drug resistant (XDR), totally drug resistant (TDR) bacteria and superbugs that have complicated the treatment of infectious diseases. Methicillin–resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) recognized as the bane of hospitals are some of the most dreaded bugs. This chapter discusses various mechanisms of multiple drug resistance (MDR) in bacteria and the limitations of antibacterial chemotherapy due to MDR. Various innate and acquired mechanisms of drug resistance like integrons, SXT elements, efflux pumps and quinolone resistance mechanisms are described in details. Some of the important databases related to these genetic factors have also been described here. The possibility of attacking the virulence of bacteria rather than the bug itself in order to circumvent the crisis of MDR has been discussed. It further highlights some of the novel strategies such as efflux pump inhibition and quorum sensing inhibition as anti-virulence strategies. It is advocated that this never-ending war with bacteria would probably require multifaceted approach combining antibacterial, antivirulent regimes in addition to the constant search for novel drug targets and newer drugs by the pharmaceutical companies. Success of these strategies would involve cumulative and strenuous efforts from public, policy makers, research community, clinicians and pharmaceutical companies.

As basic knowledge regarding the molecular biology of viruses and their interactions with their hosts improves, virus expression vectors increase in sophistication and their applications in the field of medicine broadens. Virus expression vectors have been used as research tools for generating vaccines and have functioned as delivery vehicles for siRNAs, antiviral agents, and other drug candidates. In this review, vectors based on poxvirus, adeno-associated virus, lentivirus and plant viruses are discussed and examples of their applications are provided. Recent innovations with respect to the use of virus expression vectors for the delivery of vaccines or for passive immunization against infectious diseases are outlined. The review concludes with a summary of the current successes and the future challenges that must be addressed for virus vaccine vectors to be utilized for research and medical treatment purposes in the years to come.

The continual emergence of viral pathogens highlights the need for effective vaccine systems that can rapidly adapt to changing or novel pathogens. The use of Newcastle disease virus (NDV)-based vector vaccines may be one of the most feasible approaches for achieving protection against such pathogens. ND is one of the most important infectious diseases of poultry. However, the use of this poultry pathogen as a vaccine vector to offer protection against other pathogens has become of interest to researchers worldwide. For example, a study has demonstrated that an NDV-based influenza A virus (H5N1) vaccine could provide complete protection of chickens and mice from lethal challenge of homologous and heterologous H5N1 avian influenza viruses. Furthermore, naturally occurring strains of NDV have demonstrated oncolytic therapeutic potency in preclinical and clinical studies. With the development of reverse genetics technology, modifications of oncolytic NDVs resulting in increased targeting and oncolytic potency become feasible. Such strategies may become a promising novel therapeutic approach against cancers. Therefore, NDV can be used as a vaccine vector to immunize against emerging or reemerging pathogens and may have great potential to be used for cancer treatment in the future.

Leishmaniasis is a group of diseases caused by protozoa of the genus Leishmania. The disease is transmitted to humans via bites of female phlebotomies sand flies that are infected with Leishmania parasites. Leishmaniasis affects 12 million people in the world, and it is known that nearly 350 million people are under risk of infection. Leishmania parasites are responsible for cutaneous, mucocutaneous, and visceral forms of Leishmaniasis. Every year, approximately 1.5 million Cutaneous Leishmaniasis (CL) and 500,000 Visceral Leishmaniasis cases are reported in the world. Due to several factors such as cross-country travel, co-infections between human immunodeficiency virus (HIV) and Leishmaniasis, resistance to antileishmanial drugs in parasites, resistance to insecticides in vectors, and global warming, all types of Leishmaniasis are rapidly spreading all around the world. In order to combat Leishmaniasis, various approaches such as vaccine development, chemotherapy, physical treatment methods, immunotherapy, applications of natural plant products, phototherapy, and nanotechnologic approaches are used in the treatment. In this review, we will mention these approaches, which compose the basis of anti-infective therapy against Leishmaniasis and suggest new future perspectives for treatment of this serious disease.

Proanthocyanidins exist as a part of a particular group of polyphenolic compounds known as flavanols. They are commonly occurring plant metabolites generally available in many sources such as fruits, bark, leaves and seeds of plants. They possess monomers, oligomers and polymers of varying molecular sizes composed of flavan-3-ols that serve as the building blocks. These compounds have been reported to have anti-carcinogenic, anti-inflammatory, anti-allergic, antioxidant, antibacterial and antiviral properties in human beings. This review will primarily focus on the in silico and in vitro analyses that verify antiviral activity of proanthocyanidins against several viruses, primarily the dengue virus.