Current Topics in Medicinal Chemistry - Volume 17, Issue 3, 2017

The invading microbial pathogens are controlled by the rapid and effective innate immune responses sequentially formation of the long-lasting adaptive memories. Toll-like receptors (TLRs) play a vital role in innate and adaptive immune response by function as a bridge to modulate the immune response. Further, genetic studies in human or animals showed that regulation of TLR signaling contributes to the antibacterial efficacy, and developing novel reagent to modulate TLR related immune response becomes an interesting therapy method to against bacterial infections. Herein we review the recent developments of this area, focusing on the reagent of synthetic molecules, natural products and peptides (or proteins), as TLR-related antibacterial drugs.

High lethality of infections caused by Listeria monocytogenes still remains a major clinical problem in spite of their susceptibility to a wide spectrum of antibiotics. The refractoriness towards treatment is primarily due to its amazing capacity to invade non-phagocytic cells and replicate there in, imparting the dual protection from immune response and antimicrobials. Therefore, generating new anti-infective drugs against intracellular infections has emerged as an urgent issue in the therapeutics of listeriosis. Researches have demonstrated that, internalization of Listeria monocytogenes into nonphagocytic cells is mediated by the interactions between the two bacterial invasion proteins, InlA and InlB, and their cellular surface receptors, E-cadherin and c-Met. As InlB promotes entry into various cell types, such as hepatocytes, epithelial cells and endothelial cells, targeting of InlB-c-Met mediated invasion is important for specifically blocking their intracellular infection. Furthermore, our preliminary in vitro studies have shown that a GA (Geldanamycin, GA) analogue, 17-AAG (tanespimycin) which is widely used in cancer therapy have important therapeutic potential by significantly enhancing the capacity of ampicillin to kill intracellular L. monocytogenes, and to protect the infected HBMECs from the cytocidal effects of this bacterium. We report here, the feasibility of tanespimycin as a potential anti-intracellular infective drug and its clinical relevance in a broader prospective, including the significant advancements in therapeutic approaches, drug effectiveness and toxicity. Exploring the therapeutic effects of c-Met inhibitors such as tanespimycin on L. monocytogenes intracellular infection may provide an alternative novel strategy for the development of antimicrobial agents for treatment of infectious diseases.

The discovery of antibiotics is one of the most significant milestones in modern medicine. Upon the advent of the antibiotic era, invasive surgical procedures, which were previously deemed too risky because of the possibility of bacterial infection, became a reality. In the process, medicine as a whole made great strides that led to the rise of the average human life span by almost three decades. Unfortunately, over the course of time bacteria have started to evolve resistance to antibiotic agents being administered, thus rendering many of these drugs ineffective (or on the verge of being ineffective). Today, the number of antibiotic-resistant bacteria continues to escalate and yet the number of new antibiotics being approved for clinical use has drastically decreased. The combination of these two factors has brought about a primary public health crisis for the 21st century. In order to maintain the status quo of modern medicine, new antibiotics need to be discovered and developed. Two emerging new strategies that hold considerable promise is the use of immunomodulator antibiotics and infection tolerance agents. Rather than targeting the bacteria directly, as traditional antibiotics do, these agents function to clear or tolerate infections by interfering with the bacterial colonization process and by stimulating the immune system of infected host. This review focuses on the different types of immunomodulation antibiotics and infection tolerance strategies that have been discovered over the last two decades and the mechanisms by which they act upon the host system to effectively combat bacterial infections.

Polymeric Quaternary Ammonium Compounds (polyQACs) comprise a broad class of materials with applications in medical implants, food processing, and surface sanitizing, amongst many others. These polymeric substances are especially promising due to their potent antibacterial activity and limited hemolytic toxicity. In particular, many polyQACs have superior therapeutic indices and a lower likelihood of developing antibacterial resistance in comparison to their monomers, making them ideal materials for wound dressings, catheters, and other biomedical applications. This review outlines the history and development, previous successes, current state of the research, and future directions of polyQACs in society.

Owing to their inherent structural features, certain sulfated glycans isolated from terrestrial or marine mammals or invertebrates, can exert therapeutic properties against infections caused by pathogenic microorganisms like bacteria, virus, fungus, and protozoan parasites. These sulfated glycans belong to a variety of classes including glycosaminoglycans (GAGs) like chondroitin sulfate, fucosylated chondroitin sulfate, dermatan sulfate, unfractionated heparin, low-molecular-weight heparin, and acharan sulfate; and the less-famous algal polysaccharides known as sulfated fucans (including fucoidans), sulfated galactans (agarans and carrageenans), and sulfated heteropolysaccharides. Administration at certain concentrations of the antimicrobial sulfated glycans, especially those containing the higher amounts of the bioactive structural requirements, can lead to the interruption or disruption of the pathogen protein-host GAG complex formation, leading thus to the decrease or impairment of the microbial binding onto host cells. This report aims at presenting the current background concerning the therapeutic effects of the above-mentioned sulfated glycans as new antimicrobial agents. When sufficient data are available, discussion regarding structure-activity relationship is provided.

Urinary tract infections are common infectious diseases which can occur in any part of the urinary tract such as bladder, kidney, ureters, and urethra. They are commonly caused by bacteria that enter through the urethra. Urinary tract infections commonly develop in the bladder and spread to renal tissues. Up to now, there are different antimicrobial agents which have beneficial role on urinary tract infections. However, most of them cause different adverse effects and therefore, much attention has been paid to the search for effective therapeutic agents with negligible adverse effects. Cranberry is known as one of the most important edible plants, which possesses potent antimicrobial effects against the bacteria responsible for urinary tract infections. Growing evidence has shown that cranberry suppresses urinary tract infections and eradicates the bacteria. Therefore, the aim of this study is to critically review the available literature regarding the antimicrobial activities of cranberry against urinary tract infection microorganisms. In addition, we discuss etiology, epidemiology, risk factors, and current drugs of urinary tract infections to provide a more complete picture of this disease.

Patients with human immunodeficiency virus (HIV) receive antiretroviral therapy (ART) through the use of antiretroviral drugs. A combination of at least three drugs that suppress HIV replication is used as standard treatment, and this is often called “highly active antiretroviral therapy” (HAART). Virus resistance is less likely when three or more drugs are used. A complication of anti- HIV drugs has a complex pharmacokinetic profile which is involved with extensive metabolism and transport by drug metabolizing enzymes (e.g., CYPs, SULTs and UGTs) and transporters (e.g., ABC and SLC). Severe drug-drug interactions (DDIs) can occur with combinations of antiretroviral drugs and this can lead to treatment failure or drug-induced toxicities. Previous reviews have focused on the role of CYPs and ABC transporters with use of antiretroviral drugs and their contributions to DDIs. In this review, we systematically and comprehensively explain the roles of enzymes (including CYPs, UGTs and SULTs) and transporters (including ABC and SLC) on all antiretroviral drugs listed on the FDA’s website. We also identify the DDIs that have been shown to be clinically important and associated with drug metabolism and transport alterations. Furthermore, we discuss herb-drug interactions that have been shown with long-term HAART when an herb is used to reduce side effects.

Ebola virus (EBOV) is a highly pathogenic virus causing severe hemorrhagic fever with a high case fatality rate of 50% - 90% in humans. Without an approved vaccine or treatments, Ebola outbreak management has been limited to palliative care and barrier methods to prevent transmission. These approaches, however, have yet to end the 2014 outbreak of Ebola after its prolonged presence in West Africa. As with the increase of outbreaks, a significant effort has been made to develop promising countermeasures for the prevention and treatment of Ebola virus infection. In this review, development of therapeutics and potential inhibitors for Ebola virus infection will be discussed.

Dengue fever, a type of global and tropical infectious disease, and its prevention has become a challenging issue worldwide. Antibody-dependent enhancement effects and the virus pathogenic mechanism have not yet been fully elucidated, hindering the development of dengue fever prevention and suitable drug treatment. There is currently no specific prevention and therapy in clinical trials, however, in recent years, studies have focused on the pathogenesis and treatment of dengue. Research focusing on dengue virus nonstructural protein in special drugs for the prevention and control of dengue fever is a new progress leading to improved understanding regarding the prevention and control of dengue fever and suitable drugs for the treatment. The main challenges regarding the structure of dengue virus nonstructural protein and the drugs for antiviral therapy are summarized in this paper.