Microbiology and Molecular Biology Reviews最新文献

SUMMARYAntibiotic resistance is a major global health threat, with an estimated 1.14 million deaths in 2021 linked to antibiotic resistance. Mutations naturally arise as bacteria evolve to defend against and survive various environmental challenges, including those exerted by antibiotics. Both overuse and misuse of antibiotics can accelerate selection for resistant bacteria. Misuse can happen when antibiotic treatment ends prematurely, resulting in sub-lethal antibiotic levels. This provides an ideal environment for the proliferation of resistance-causing mutations, which, in some cases, are enhanced further by triggering the synthesis of error-prone DNA polymerases. Low levels of antibiotics are also found in the environment, creating breeding grounds for the evolution of antibiotic resistance. Mutations diminish the impact of antibiotics by three principal mechanisms: (i) reducing antibiotic influx, (ii) elevating antibiotic efflux, and (iii) altering cellular targets of antibiotics. The first two mechanisms confer modest resistance against a broad range of antibiotics; however, in combination with the third target-specific mechanism, they become the foundation of high-level antibiotic resistance. Ultimately, while the manifestation of mutations cannot be prevented, steps can be taken to lower their frequency by carefully considering the need for antibiotic prescription, exploring combination therapies, integrating adjuvants such as efflux pump inhibitors, and minimizing environmental contamination of antibiotics.

SUMMARYThe high mortality associated with invasive fungal infections, coupled with limited therapeutic options, underscores the urgent need for antifungal agents with novel mechanisms of action. Natural products represent a particularly valuable resource, providing structurally diverse and evolutionary refined scaffolds that often outperform those found in synthetic libraries. Historically, microorganisms have proven to be a rich source of antibiotics and other therapeutic agents. Access to diverse phylogenetic lineages and biosynthetic pathways has been essential for antifungal drug development. In this review, we highlight the chemical and biosynthetic diversity of antifungal natural products derived from both fungi and bacteria. We emphasize that microbial natural products continue to play a crucial role in antifungal development, particularly through the integration of natural product chemistry, microbiology, genetics, and advanced omics technologies.

SUMMARYBotulism is a neuroparalytic intoxication caused by a collection of large proteins, known as botulinum neurotoxins (BoNTs), that are related in amino acid sequence and structure. The extreme potency of BoNTs can be traced to their ability to access and enter cholinergic nerve terminals, their enzymatic nature, and their persistence within these cells. The extreme diversity seen among the BoNTs (7 serotypes and 44 subtypes) and the bacteria that produce them (7 species) stands in stark contrast to its close relative, tetanus toxin, which exists as a single protein entity produced by a single bacterial strain. Botulism may take many forms. It can be due to direct ingestion with BoNT (foodborne), or it may be the consequence of germination and toxin production within the body (infant and adult toxicoinfections, wound botulism). As BoNT-producing organisms are soil inhabitants, the cycle that results in botulism begins when the spores of these bacteria are moved to a location that is favorable for its growth and toxin production, be that in foods, humans, or animals. Multiple researchers in the United States did pioneering work concerning the etiology of botulism, including the identification of different types, the recognition of various host sensitivities, and the necessary conditions for germination and toxin production of these bacteria. As part of their work, several large collections of BoNT-producing bacteria were amassed. This review is a culmination of historical events relating to botulism in the United States and provides listings containing source information on strains from various collections that have provided valuable reference bacteria for basic research studies on botulism and the development of diagnostic tests, quality control testing, and botulism treatments and countermeasures, such as antisera and vaccines.

SUMMARYCryptosporidiosis is a major public health concern, the extent of which has only truly been appreciated within the last decade. Cryptosporidium research has undergone a renaissance, with new insights into population structure, species diversity, and evolution of the parasite driven by the advent of genetic transformation techniques and novel models for culture in vitro and in vivo. Here, we summarize the impact of these advances on our understanding of this important parasite. In the initial section, we focus on what we have learned about host range and infectivity from comparative genomics, briefly review the public health impact of human infection, and summarize recent findings on immune control and interactions with other gut microbes that influence infection. The second half of the review is devoted to new technical advances that have uncovered novel biological findings. As research on Cryptosporidium is still in its infancy, we finish by summarizing some of the challenges and opportunities for future research.

SUMMARYBacterial cell walls are made up of peptidoglycan (PG), a primary load-bearing layer that forms a protective exoskeleton around the cytoplasmic membrane. PG is a heteropolymer composed of glycan chains attached to short peptides that are crosslinked to each other, forming a mesh-like macromolecule that prevents osmotic lysis of the cell. Far from being a static exoskeleton, PG is a dynamic living polymer that undergoes continuous synthesis, expansion, remodeling, and turnover throughout the bacterial cell cycle. Central to the dynamic nature of PG is a finely tuned balance between two seemingly opposite processes-synthesis and hydrolysis. The PG synthases, which are essential for bacterial viability, have long been recognized as excellent drug targets and have therefore been studied extensively for decades. On the other hand, the significance of PG hydrolysis in diverse fundamental PG processes has become increasingly evident in recent years. Bacteria encode several highly conserved PG hydrolases with distinct substrate specificities that contribute to critical cellular processes, including cell wall expansion during growth, cell division, remodeling, and recycling, as well as predation and pathogenesis. Consequently, PG hydrolases represent promising targets for the development of novel antibacterial therapeutics. This review provides a comprehensive overview of the classification, physiological functions, and regulatory mechanisms governing the PG hydrolases in the model organism Escherichia coli and highlights parallels among related taxa across the bacterial kingdom.

SUMMARYThe primary objective of this review is to provide an update on the most recent findings concerning the adverse effects of Shiga toxin-producing Escherichia coli (STEC) on the central nervous system (CNS), from both clinical and experimental perspectives. Considered the main predictor of death, STEC encephalopathy plays a critical role in hemolytic uremic syndrome (HUS), which affects between 11% and 64% of HUS patients and considerably increases the risk of morbidity and mortality. Of note, STEC encephalopathy in the absence of HUS has been observed in approximately 5% of cases. The ability of enterohemorrhagic E. coli to adapt to its microenvironment has been responsible for global outbreaks. Once in circulation, Shiga toxin rapidly induces endothelial damage via the Gb3 receptor. Brain inflammation in STEC encephalopathies has been consistently reported and experimentally confirmed. The entry of Shiga toxin into the brain leads to direct neuronal damage through its interaction with neuronal Gb3, as demonstrated in clinical case studies and experimental models. This review also discusses the adverse effects of STEC on the brain, which may arise from metabolic or circulatory disruptions, secondary damage to the CNS, or a multifactorial combination. Recent studies have highlighted the significance of neuroimaging techniques in diagnosing HUS encephalopathy. Efforts have been made to identify early neural biomarkers and develop corresponding treatments. Although various biomarkers have been reported, additional studies are needed for further development and standardization. Late-stage pharmacological treatments for encephalopathy are also discussed, both in clinical settings and experimental research.

SUMMARYMeningoencephalitis is the most severe form of cryptococcal infection. Pathogenic cryptococcal species enter the body primarily via the respiratory system. The central nervous system (CNS) is by far the most common site of cryptococcal dissemination, despite its reputation as a privileged anatomical space. Results from both in vitro and in vivo experiments have suggested multiple cellular and molecular mechanisms for entering the CNS, but no single one has been proven responsible for this remarkable neurotropism. While experimental approaches to the problem have centered around a uniform conception of the blood-brain barrier, a review of the histopathological forms of CNS disease shows marked variety in the locations and forms of lesions and their relevant anatomical barriers. Based on the microanatomy, it is likely that the pathway from blood into the CNS differs from lesion type to lesion type. In considering the genesis of cryptococcal CNS infection, we will first summarize cryptococcal virulence determinants of relevance to CNS infection and the conceptualization of the blood-brain barrier, its history, and functions. Next, we will summarize modes of cryptococcal entry through the blood-brain barrier and the interplay between fungal virulence determinants and host factors. We will outline the common histological findings of cryptococcal meningoencephalitis and examine the relevant vascular structures, discussing their implications for mechanisms of dissemination in the context of the vasculature, the host cellular and metabolic environment, and cryptococcal virulence factors in different parts of the CNS. Finally, we will discuss the value of different animal and in vitro models of cryptococcal infection and the endothelial glycocalyx, a ubiquitous feature of endothelial surfaces seldom considered in microbial pathogenesis.

SUMMARYBacteria are frequently subject to potentially lethal temperature shifts in their natural environments. We review the changes in the structure and dynamics of the gene regulatory network of the bacterium Escherichia coli during cold shocks. First, we describe the effects of cold shocks on higher-order cellular structures (cytoplasm and membrane) and functions (growth, division, and biofilm formation). Next, we focus on the nucleoid, DNA supercoiling, topoisomerases, ATP, and nucleoid-associated proteins. Afterward, we describe the mutual effects of changes in transcription dynamics and DNA supercoiling during cold shocks, followed by the consequent genome-wide, time-lapse changes in the transcriptome. Finally, we briefly describe the post-transcriptional effects of cold shocks and the cellular processes of acclimatization. In the end, we discuss how studying this topic can assist in developing temperature-sensitive synthetic genetic circuits, efficient bioindustrial processes, and new means to cope with bacterial antibiotic tolerance.

SUMMARYIn fungi, the endomembrane system is a pleiomorphic, dynamic network of organelles, driven by vesicle trafficking pathways, which maintain cellular homeostasis, hyphal polar growth, and the secretion of proteins and metabolites. In syncytial hyphae, spatial specialization of organelles and other cellular components of the endomembrane system is evident to support growth and adaptation. Young, apical regions of hyphae contain a Golgi-Spitzenkörper-exocyst triad for rapid polar expansion, whereas distal, older hyphal regions employ unconventional secretion via multivesicular bodies (MVBs), septal vesicle fusion, and extracellular vesicles (EVs) to enhance nutrient acquisition for the entirety of the mycelium. Vesicular trafficking integrates distinct endomembrane compartments into specialized pathways that involve vesicle biogenesis, transport, and fusion to sustain polarized growth and secretion. Actin and microtubules provide tracks for vesicle motility, while Rab GTPases regulate vesicle localization and fusion events. The ESCRT machinery governs MVB formation and scission, COPI/II regulate bidirectional endoplasmic reticulum-Golgi transport, SNARE proteins allow for vesicle and target membrane fusion, and the exocyst complex tethers vesicles to exocytic regions of the plasma membrane. Together, these components form dynamic endomembrane assembly lines that coordinate many cellular processes. The "distance hypothesis" predicts that extracellular vesicle-mediated secretion predominates in subapical regions as tip growth slows. This mechanism extends the secretory capabilities of hyphae and promotes broader distribution of secreted enzymes along hyphae. Having a better understanding of spatially regulated secretion pathways will advance our understanding of fungal cell biology and provide strategies to optimize fungi for industrial protein production.

SUMMARYDespite advancements in antiretroviral therapy, people living with HIV (PLWH) remain at high risk of lymphoma. The persistence of HIV reservoirs and their spatial association with lymphoma highlights the need to clarify their role in lymphomagenesis. HIV reservoirs, which are established early during infection and maintained through clonal expansion, epigenetic silencing, and immune evasion, may contribute to lymphomagenesis through four interconnected mechanisms: provirus integration effects, viral protein-mediated disturbances, microenvironment dysregulation, and reservoir reactivation. Current therapeutic approaches that simultaneously target HIV reservoirs and lymphoma-including allogeneic hematopoietic stem cell transplantation, chimeric antigen receptor T-cell therapy, and immune checkpoint inhibitors-show promise but face substantial challenges. There is an urgent need to develop accessible strategies that can both eradicate HIV reservoirs and mitigate lymphoma risk. Such efforts may ultimately enable a "double cure" for PLWH with lymphoma, offering new hope against this life-threatening comorbidity. This review summarizes the potential links between HIV reservoirs and HIV-associated lymphoma and outlines emerging therapeutic avenues toward achieving a double cure.