Essays in biochemistry最新文献

Hormones play pivotal roles in our well-being, and even more so in times of stress or disease. They determine body composition and govern reproductive processes. Hormonal compounds tend to be evolutionarily very old compounds, but only coevolved receptor systems make up powerful biological signals. We will discuss what makes some metabolites good building materials for hormones and how information may be encoded, using these scaffolds. Starting with hormone biosynthesis and regulated release from secreting cells, we will look at different stages of the whole hormone signaling process: the distribution of the hormonal "message-in-a-bottle" throughout the body, the passing of some hormones through membranes, and pre-receptor metabolism. Binding to different classes of receptors is not the end of hormone signaling, but the beginning of a second phase of signaling via second messengers, before hormonal messages are switched off again. Studying hormone biochemistry will produce exciting new findings in the future.

One Health aims to bring together human, animal, and environmental research to achieve optimal health for all. Bacteriophages (phages) are viruses that kill bacteria and their utilisation as biocontrol agents in the environment and as therapeutics for animal and human medicine will aid in the achievement of One Health objectives. Here, we assess the diversity of phages used in One Health in the last 5 years and place them in the context of global phage diversity. Our review shows that 98% of phages applied in One Health belong to the class Caudoviricetes, compared to 85% of sequenced phages belonging to this class. Only three RNA phages from the realm Riboviria have been used in environmental biocontrol and human therapy to date. This emphasises the lack in diversity of phages used commercially and for phage therapy, which may be due to biases in the methods used to both isolate phages and select them for applications. The future of phages as biocontrol agents and therapeutics will depend on the ability to isolate genetically novel dsDNA phages, as well as in improving efforts to isolate ssDNA and RNA phages, as their potential is currently undervalued. Phages have the potential to reduce the burden of antimicrobial resistance, however, we are underutilising the vast diversity of phages present in nature. More research into phage genomics and alternative culture methods is required to fully understand the complex relationships between phages, their hosts, and other organisms in the environment to achieve optimal health for all.

Bacteriophages, viruses that infect bacteria, play a crucial role in manipulating the gut microbiome, with implications for human health and disease. Despite the vast amount of data available on the human gut virome, the number of cultured phages that infect human gut bacteria-particularly obligate anaerobes-remains strikingly limited. Here, we summarize the resources and basic characteristics of phages that infect the human gut obligate anaerobe. We review various methods for isolating these phages and suggest a strategy for their isolation. Additionally, we outline their impact on the field of viral biology, their interactions with bacteria and humans, and their potential for disease intervention. Finally, we discuss the value and prospects of research on these phages, providing a comprehensive 'Roadmap' that sheds light on the 'dark matter' of phages that infect human gut obligate anaerobes.

Bacteria host various foreign genetic elements, most notably plasmids and bacteriophages (or phages). Historically, these two classes were seen as separate, but recent research has shown considerable interplay between them. Phage-plasmids (P-Ps) exhibit characteristics of both phages and plasmids, allowing them to exist extrachromosomally within bacterial hosts as plasmids, but also to infect and lyse bacteria as phages. This dual functionality enables P-Ps to utilize the modes of transmission of both phage and plasmids, facilitating the rapid dissemination of genetic material, including antibiotic resistance and virulence genes, throughout bacterial populations. Additionally, P-Ps have been found to encode toxin-antitoxin and CRISPR-Cas adaptive immune systems, which enhance bacterial survival under stress and provide immunity against other foreign genetic elements. Despite a growing body of literature on P-Ps, large gaps remain in our understanding of their ecological roles and environmental prevalence. This review aims to synthesise existing knowledge and identify research gaps on the impacts of P-Ps on microbial communities.

Klebsiella pneumoniae is an opportunistic pathogen with significant clinical relevance. K. pneumoniae-targeting bacteriophages encode specific polysaccharide depolymerases with the ability to selectively degrade the highly varied protective capsules, allowing for access to the bacterial cell wall. Bacteriophage depolymerases have been proposed as novel antimicrobials to combat the rise of multidrug-resistant K. pneumoniae strains. These enzymes display extraordinary diversity, and are key determinants of phage host range, however with limited data available our current knowledge of their mechanisms and ability to predict their efficacy is limited. Insight into the resolved structures of Klebsiella-specific capsule depolymerases reveals varied catalytic mechanisms, with the intra-chain cleavage mechanism providing opportunities for recombinant protein engineering. A detailed comparison of the 58 characterised depolymerases hints at structural and mechanistic patterns, such as the conservation of key domains for substrate recognition and phage tethering, as well as diversity within groups of depolymerases that target the same substrate. Another way to understand depolymerase specificity is by analyzing the targeted capsule structures, as these may share similarities recognizable by bacteriophage depolymerases, leading to broader substrate specificities. Although we have only begun to explore the complexity of Klebsiella capsule depolymerases, further research is essential to thoroughly characterise these enzymes. This will be crucial for understanding their mechanisms, predicting their efficacy, and engineering optimized enzymes for therapeutic applications.

Phage therapy has attracted attention again owing to the increasing number of drug-resistant bacteria. Although the efficacy of phage therapy has been reported, numerous studies have indicated that the generation of phage-specific antibodies resulting from phage administration might have an impact on clinical outcomes. Phage-specific antibodies promote phage uptake by macrophages and contribute to their rapid clearance from the body. In addition, phage-specific neutralizing antibodies bind to the phages and diminish their antibacterial activity. Thus, phage-specific antibody production and its role in phage therapy have been analyzed both in vitro and in vivo. Strategies for prolonging the blood circulation time of phages have also been investigated. However, despite these efforts, the results of clinical trials are still inconsistent, and a consensus on whether phage-specific antibodies influence clinical outcomes has not yet been reached. In this review, we summarize the phage-specific antibody production during phage therapy. In addition, we introduce recently performed clinical trials and discuss whether phage-specific antibodies affect clinical outcomes and what we can do to further improve phage therapy regimens.

The growing threat of antimicrobial resistant (AMR) bacterial pathogens coupled with the relative dearth of promising novel antibiotics requires the discovery and development additional medical interventions. Over the past decade bacteriophages have emerged one of the most promising new tools to combat AMR pathogens. Anecdotal clinical experiences under so-called 'compassionate use' regulatory pathways as well as a limited number of clinical trials have provided ample evidence of safety and early evidence of efficacy. For phages to reach their full potential it is critical that rigorous clinical trials be conducted that define their optimal use and that enable regulatory authorities to support the commercialization required to afford global access. The clinical development of phage therapeutics requires the design and execution of clinical trials that take full advantage of lessons learned from a century of antibiotic development and that use clinical investigation as a platform in which aspects of phage biology that are critical to therapeutics are more clearly elucidated. Translational research that elucidates phage biology in the context of clinical trials will promote highly relevant hypothesis-driven work in basic science laboratories and will greatly accelerate the development of the field of phage therapeutics.

The discovery of viruses that can devour bacteria, bacteriophages (phages), was in 1915. Phages are ubiquitous, outnumbering the organisms they devour, and genomically, morphologically, and ecologically diverse. They were critical in our development of molecular biology and biotechnology tools and have been used as therapeutics for over 100 years, primarily in Eastern Europe with thousands of patients from all over the world treated in Georgia. The rise of antimicrobial resistance and the lack of new antimicrobials, has brought them back into the spotlight dawning the New Age of the Phage. This special issue will provide further insight to phage diversity across ecosystems, including humans, animals, and plants, i.e. the basis of a One Health approach, and the requirements for turning phages into viable medicines for the many and not just for the few.

Antimicrobial resistance (AMR) poses a significant global health threat, as it contributes to prolonged illness, higher mortality rates and increased healthcare costs. As traditional antibiotics become less effective, treatments such as bacteriophage therapy offer potential solutions. The question remains, however, on how to set research priorities in the face of a growing number of antibiotic-resistant pathogens, some common and/or dangerous. One standard way of making decisions about which research to prioritise is by using the disability-adjusted life year metric to estimate the current global impact of a disease or condition, combined with considerations of social justice although decisions made at a national level by governments, especially in low income countries with forecasting potential over future needs may look very different. Another approach is based on the needs of researchers and regulators given what we know about the technology itself. The biological characteristics of bacteriophage therapies set challenges to a universal and standardised prioritisation method. A proof of principle is still arguably needed. With a preliminary discussion of the scope and complexity of AMR and AMR therapeutics, we propose some implications of regulatory frameworks aiming to integrate bacteriophage therapy into mainstream medical practice while gathering scientific data on safety and efficacy, enhancing the collective action needed to combat AMR.

Phage lysins, bacteriophage-encoded enzymes tasked with degrading their host's cell wall, are increasingly investigated and engineered as novel antibacterials across diverse applications. Their rapid action, tuneable specificity, and low likelihood of resistance development make them particularly interesting. Despite numerous application-focused lysin studies, the art of their recombinant production remains relatively undiscussed. Here, we provide an overview of the available expression systems for phage lysin production and discuss key considerations guiding the choice of a suitable recombinant host. We systematically surveyed recent literature to evaluate the hosts used in the lysin field and cover various recombinant systems, including the well-known bacterial host Escherichia coli or yeast Saccharomyces cerevisiae, as well as plant, mammalian, and cell-free systems. Careful analysis of the limited studies expressing lysins in various hosts suggests a host-dependent effect on activity. Nonetheless, the multitude of available expression systems should be further leveraged to accommodate the growing interest in phage lysins and their expanding range of applications.