Current Medicinal Chemistry - Volume 24, Issue 36, 2017

Trimethylamine-N-oxide (TMAO) is a low molecular weight metabolite whose production is dependent on metabolism of its precursors choline, carnitine, creatinine, betaine or lecithin by host gut microbes resulting in the synthesis of trimethylamine (TMA), which is subsequently oxidized to TMAO via hepatic flavin monooxygenase (FMO). TMAO is associated with microbial dysbiosis and is being studied for its linkage with cardiovascular disorders. In addition, dysregulated levels of TMAO have been linked with renal diseases, neurological disorders and cancer. Here we discuss the enzymatic and metabolic landscape that results in TMAO production, and in addition, collate data from numerous clinical studies that have assessed TMAO as a biomarker for various disease conditions. We also summarize the interaction of TMAO with modern and traditional drugs that together affect circulating TMAO levels in the human body.

Tuberculosis is a leading killer, especially for people living with HIV. It is a real medical need to tackle this disease, which is made difficult to treat due to the increasing spread of multi-drug-resistant and extensively drug-resistant bacterial strains. Cases of tuberculosis that are resistant to virtually all drugs currently available are increasing at an alarming rate around the world. Here, we review the current knowledge in the field of drug development against tuberculosis with a focus on the mechanisms of action of drugs and the targeted bacterial cell processes involved. Particular emphasis is dedicated to the process of cell wall synthesis, which has proven to provide strong potentialities for drug development. It is hoped that a deeper understanding of key molecular machineries to tackle will provide us with a better outline of possible antibacterial mechanisms of action and offer hints for the design of more efficient strategies to treat resistant tuberculosis in the future.

Universal stress proteins are ubiquitously expressed in bacteria, archaea and plants and other eukaryotes. A general property of USPs is their role in adaptation of bacteria to oxidative stress, high temperature, low pH and/or hypoxia. There is increasing evidence that these proteins facilitate the adaption of bacterial pathogens to the human host environment, thereby facilitating colonisation and pathogenicity. USPs in Mycobacterium tuberculosis are well studied and may play a role in latency of tuberculosis. USP expressed by Acinetobacter baumannii, Listeria monocytogenes and Salmonella enterica serovar Typhimurium are involved in survival in vivo, while USPs expressed in Pseudomonas aeruginosa and Porphyromonas gingivalis are involved in biofilm formation. Burkholderia cepacia complex and Staphylococcus aureus express USPs that play roles in host cell or host protein adhesion. There is also increasing evidence that USPs also bind to antimicrobial agents and may be ideal candidates to target in the future design of new anti-virulence strategies.

Pattern recognition receptors on the plant cell surface mediate the recognition of microbe-associated molecular patterns, in a process which activates downstream immune signaling. These receptors are plasma membrane-localized kinases which need to be autophosphorylated to activate downstream responses. Perception of attacks from fungi occurs through recognition of chitin, a polymer of an N-acetylglucosamine which is a characteristic component of the cell walls of fungi. This process is regulated in Arabidopsis by chitin elicitor receptor kinase CERK1. A more complex process characterizes rice, in which regulation of chitin perception is operated by a complex composed of OsCERK1, a homolog of CERK1, and the chitin elicitor binding protein OsCEBiP. Recent literature has provided a mechanistic description of the complex regulation of activation of innate immunity in rice and an advance in the structural description of molecular players involved in this process. This review describes the current status of the understanding of molecular events involved in innate immunity activation in rice.

Bacteriophages (phages or bacterial viruses) are the most abundant biological entities in our planet; their influence reaches far beyond the microorganisms they parasitize. Phages are present in every environment and shape up every bacterial population in both active and passive ways. They participate in the circulation of organic matter and drive the evolution of microorganisms by horizontal gene transfer at unprecedented scales. The mass flow of genetic information in the microbial world influences the biosphere and poses challenges for science and medicine. The genetic flow, however, depends on the fate of the viral DNA injected into the bacterial cell. The archetypal notion of phages only engaging in predatorprey relationships is slowly fading. Because of their varied development cycles, environmental conditions, and the diversity of microorganisms they parasitize, phages form a dense and highly complex web of dependencies, which has important consequences for life on Earth. The sophisticated phage-bacteria interplay includes both aggressive action (bacterial lysis) and “diplomatic negotiations” (prophage domestication). Here, we review the most important mechanisms of interactions between phages and bacteria and their evolutionary consequences influencing their biodiversity.

Understanding how immunity to pathogens develops is crucial for progress in the quest for effective vaccines. Intraspecies and interspecies cross-reacting antibodies are produced in high frequency against immune-relevant and shared microbial epitopes. It has been confirmed that cross-reactive antigens may have a crucial role in natural epidemiology to a particular infection and that cross-protection may influence the outcome of natural infections. On the other hand, the action of cross-reactive antibodies may be very harmful for the host. In this review we discuss both the defensive and offensive capabilities of cross-reactive antibodies. The defensive properties are discussed with regard to the beneficial cross-protective interaction of these antibodies against various microorganisms including viruses, bacteria, fungi and protozoan parasites. We summarize the current knowledge of numerous effector functions of these antibodies such as agglutination, neutralization of infectivity, complement activation, phagocytosis enhancement, and antibody-dependent cellular cytotoxicity. We also discuss the offensive action of cross-reactive antibodies including their detrimental effects in exacerbation of the infective diseases, as well as autoimmune diseases and allergy as a result of inappriopriate or deleterious inflammatory response associated with host tissue destruction. The factors influencing cross-protective capacity of antibodies are also presented.

Background: Penicillin binding proteins (PBPs) and Serine Threonine kinases (STPKs) are two classes of bacterial enzymes whose involvement in a series of vital processes in bacterial growth and division is well assessed. Many PBPs and STPKs show linked an ancillary domain named PASTA, whose functional role is not completely deciphered so far. It has been proposed that PASTAs are sensor modules that by binding opportune ligands (i.e. muropeptides) activate the cognate proteins to their functions. However, based on recent data, the sensor annotation sounds true for PASTA from STPKs, and false for PASTA from PBPs. Objective: Different PASTA domains, belonging or not to different protein classes, sharing or not appreciable sequence identities, always show identical folds. This survey of the structural, binding and dynamic properties of PASTA domains pursues the reasons why identical topologies may turn in different roles. Results: Amino acid compositions, total charges and distribution of the hydrophobic/hydrophilic patches on the surface, significantly vary among PASTAs from STPKs and PBPs and appear to correlate with different functions. A possible criterion to discriminate between PASTA modules of STPKs or PBPs solely based on their sequences is proposed. Possibly reflecting different species as well as functional roles and evolutionary profile, our routine represents a fast even though approximate method to distinguish between PASTA belonging to different classes.

Background: From the simplest bacteria to the highest complex mammals, including humans, every single cell is covered by a dense coat of glycans. Glycans are involved in almost every biological process that takes place in our body, playing a central role in the communication between cells and their environment. Glycans are also involved in infectious diseases, which arise from the specific interaction between glycans of the pathogen cell coat and specific receptors on the host cell or vice versa. Objective: The understanding of the mechanisms governing these specific carbohydrateprotein interactions, at atomic and molecular levels, is crucial to develop new drugs able to block the infection and to avoid the disease. Methods: Recent advances in biophysical techniques allow for a complete picture of the hostpathogen infection event, unveiling the key aspects of the molecular interaction and, thus, providing an opportunity to interfere with it. Conclusion: In this general review, we discuss some recent contributions, providing a summary of what we consider the most innovative and inspiring research lines to the field.

Background: HCV-linked pathologies represent worldwide health threats. Over the years, an enormous number of independent studies have been devoted to the understanding of the molecular bases of HCV infection. A significant amount of these investigations has been focused on the structural characterization of the virus proteins with the aim of developing structure-based innovative therapeutic approaches. An analysis of the current Protein Data Bank content unravels that the structural biology of the virus has hitherto covered a large fraction of the HCV proteins (75%). Objective: The present review recapitulates the state-of-the-art of structural characterizations of HCV individual proteins with a specific focus on their structural versatility/flexibility. Results: This survey indicates there is accumulating evidence that structural flexibility is a common feature among HCV proteins. This versatility can be detected at different structural level i.e. occurrence of alternative oligomeric states and/or of local and global flexibility. Somewhat surprisingly, some disordered or highly flexible regions of HCV proteins, such as the core and the antigenic fragment 412-423 of E2, present highly conserved sequences among the virus genotypes. The overall versatility of HCV proteins plays an important role in host protein recognition, drug resistance mechanisms, and virus escape from the host immunogenic system. Of particular relevance is the emerging idea that HCV uses local structural flexibility as an alternative tool to sequence variability to evade the immune response of the host organism. Conclusion: We believe that concepts emerged from this survey will be important for the development of anti-HCV vaccines that are eagerly needed.