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  • 刊频： Eighteen no. a year, 2019-
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  • 1.

    【2hr】Mechanisms of Candida biofilm drug resistance

    包量

    机译 念珠菌生物膜耐药机制
    摘要：Candida commonly adheres to implanted medical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations. As currently available antifungals have minimal activity against biofilms, new drugs to treat these recalcitrant infections are urgently needed. Recent investigations have begun to shed light on the mechanisms behind the profound resistance associated with the biofilm mode of growth. This resistance appears to be multifactorial, involving both mechanisms similar to conventional, planktonic antifungal resistance, such as increased efflux pump activity, as well as mechanisms specific to the biofilm lifestyle. A unique biofilm property is the production of an extracellular matrix. Two components of this material, β-glucan and extracellular DNA, promote biofilm resistance to multiple antifungals. Biofilm formation also engages several stress response pathways that impair the activity of azole drugs. Resistance within a biofilm is often heterogeneous, with the development of a subpopulation of resistant persister cells. In this article we review the molecular mechanisms underlying Candida biofilm antifungal resistance and their relative contributions during various growth phases.
  • 2.

    【2hr】Radioimmunotherapy of Cryptococcus neoformans sparesbystander mammalian cells

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    机译 新型隐球菌备用品的放射免疫治疗旁观者哺乳动物细胞
    摘要：AimPreviously, we showed that radioimmunotherapy (RIT) for cryptococcal infections using radioactively labeled antibodies recognizing the cryptococcal capsule reduced fungal burden and prolonged survival of mice infected with Cryptococcus neoformans. Here, we investigate the effects of RIT on bystander mammalian cells.
  • 3.

    【2hr】Progress in targeting cell envelope biogenesis in Mycobacterium tuberculosis

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    机译 结核分枝杆菌靶向细胞包膜生物发生的研究进展
    摘要：Most of the newly discovered compounds showing promise for the treatment of TB, notably multidrug-resistant TB, inhibit aspects of Mycobacterium tuberculosis cell envelope metabolism. This review reflects on the evolution of the knowledge that many of the front-line and emerging products inhibit aspects of cell envelope metabolism and in the process are bactericidal not only against actively replicating M. tuberculosis, but contrary to earlier impressions, are effective against latent forms of the disease. While mycolic acid and arabinogalactan synthesis are still primary targets of existing and new drugs, peptidoglycan synthesis, transport mechanisms and the synthesis of the decaprenyl-phosphate carrier lipid all show considerable promise as targets for new products, older drugs and new combinations. The advantages of whole cell- versus target-based screening in the perpetual search for new targets and products to counter multidrug-resistant TB are discussed.
  • 4.

    【2hr】The ferric uptake regulator of Helicobacter pylori: a critical player in the battle for iron and colonization of the stomach

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    机译 幽门螺杆菌的铁吸收调节剂：在铁和胃定植之战中的关键角色
    摘要：Helicobacter pylori is arguably one of the most successful pathogens; it colonizes the stomachs of more than half of the human population. Colonization and persistence in such an inhospitable niche requires the presence of exquisite adaptive mechanisms. One of the proteins that contributes significantly to the remarkable adaptability of H. pylori is the ferric uptake regulator (Fur), which functions as a master regulator of gene expression. In addition to genes directly related to iron homeostasis, Fur controls expression of several enzymes that play a central role in metabolism and energy production. The absence of Fur leads to severe H. pylori colonization defects and, accordingly, several Fur-regulated genes have been shown to be essential for colonization. Moreover, proteins encoded by Fur-regulated genes have a strong impact on redox homeostasis in the stomach and are major determinants of inflammation. In this review, we discuss the main roles of Fur in the biology of H. pylori and highlight the importance of this regulatory protein in the infectious process.
  • 5.

    【2hr】Pharmacology of polymyxins: new insights into an ‘old’ class of antibiotics

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    机译 多粘菌素的药理学：对“旧”类抗生素的新见解
    摘要：Increasing antibiotic resistance in Gram-negative bacteria, particularly in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, presents a global medical challenge. No new antibiotics will be available for these ‘superbugs’ in the near future due to the dry antibiotic discovery pipeline. Colistin and polymyxin B are increasingly used as the last-line therapeutic options for treatment of infections caused by multidrug-resistant Gram-negative bacteria. This article surveys the significant progress over the last decade in understanding polymyxin chemistry, mechanisms of antibacterial activity and resistance, structure–activity relationships and pharmacokinetics/pharmacodynamics. In the ‘Bad Bugs, No Drugs’ era, we must pursue structure–activity relationship-based approaches to develop novel polymyxin-like lipopeptides targeting polymyxin-resistant Gram-negative ‘superbugs’. Before new antibiotics become available, we must optimize the clinical use of polymyxins through the application of pharmacokinetic/pharmacodynamic principles, thereby minimizing the development of resistance.
  • 6.

    【2hr】Genetic diversity in the oral pathogen Porphyromonas gingivalis: molecular mechanisms and biological consequences

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    机译 口腔病原体牙龈卟啉单胞菌的遗传多样性：分子机制和生物学后果
    摘要：Porphyromonas gingivalis is a Gram-negative anaerobic bacterium that colonizes the human oral cavity. It is implicated in the development of periodontitis, a chronic periodontal disease affecting half of the adult population in the USA. To survive in the oral cavity, these bacteria must colonize dental plaque biofilms in competition with other bacterial species. Long-term survival requires P. gingivalis to evade host immune responses, while simultaneously adapting to the changing physiology of the host and to alterations in the plaque biofilm. In reflection of this highly variable niche, P. gingivalis is a genetically diverse species and in this review the authors summarize genetic diversity as it relates to pathogenicity in P. gingivalis. Recent studies revealing a variety of mechanisms by which adaptive changes in genetic content can occur are also reviewed. Understanding the genetic plasticity of P. gingivalis will provide a better framework for understanding the host–microbe interactions associated with periodontal disease.
  • 7.

    【2hr】Staphylococcus aureus and CCR5: unveiling commonalities in host–pathogen interactions and potential treatment strategies

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    机译 金黄色葡萄球菌和CCR5：揭示宿主-病原体相互作用和潜在治疗策略的共性
    摘要：Microbes that have acquired the ability to colonize and/or cause disease in humans must be able to both recognize and respond to host defenses to ensure their survival. For commensal microbes, adaptive strategies generally promote a balance between host immune defenses and bacterial maintenance, allowing asymptomatic colonization. Pathogenic microbes, on the other hand, tilt the balance in favor of the microorganism, leading to symptomatic illness and disease. Some microorganisms that are known to be asymptomatic colonizers of humans can cause serious disease upon gaining access to foreign sites and usurping immunological attack. The Gram-positive bacterium Staphylococcus aureus is one such microorganism.This article will address recent advances in our understanding of S. aureus immune evasion with an emphasis on immune cell targeting. The prospects of this targeting in terms of understanding the evolution of S. aureus as a pathogen as well as its implications for future anti-S. aureus therapeutics, will be discussed.
  • 8.

    【2hr】Stress responses in the opportunistic pathogen Acinetobacter baumannii

    包量

    机译 机会病原体鲍曼不动杆菌的应激反应
    摘要：Acinetobacter baumannii causes a wide range of severe infections among compromised and injured patients worldwide. The relevance of these infections are, in part, due to the ability of this pathogen to sense and react to environmental and host stress signals, allowing it to persist and disseminate in medical settings and the human host. This review summarizes current knowledge on the roles that environmental and cellular stressors play in the ability of A. baumannii to resist nutrient deprivation, oxidative and nitrosative injury, and even the presence of the commonly used antiseptic ethanol, which could serve as a nutrient- and virulence-enhancing signal rather than just being a convenient disinfectant. Emerging experimental evidence supports the role of some of these responses in the pathogenesis of the infections A. baumannii causes in humans and its capacity to resist antibiotics and host response effectors.
  • 9.

    【2hr】Peptide targeting and imaging of damaged lung tissue in influenza-infected mice

    包量

    机译 流感感染小鼠中靶向肽和受损肺组织的成像
    摘要：AimIn this study, we investigate whether pH (low) insertion peptide (pHLIP) can target regions of lung injury associated with influenza infection.
  • 10.

    【2hr】Factors shaping the adaptive landscape for arboviruses: implications for the emergence of disease

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    机译 形成虫媒病毒适应性格局的因素：对疾病出现的影响
    摘要：Many examples of the emergence or re-emergence of infectious diseases involve the adaptation of zoonotic viruses to new amplification hosts or to humans themselves. These include several instances of simple mutational adaptations, often to hosts closely related to the natural reservoirs. However, based on theoretical grounds, arthropod-borne viruses, or arboviruses, may face several challenges for adaptation to new hosts. Here, we review recent findings regarding adaptive evolution of arboviruses and its impact on disease emergence. We focus on the zoonotic alphaviruses Venezuelan equine encephalitis and chikungunya viruses, which have undergone adaptive evolution that mediated recent outbreaks of disease, as well as the flaviviruses dengue and West Nile viruses, which have emerged via less dramatic adaptive mechanisms.
  • 11.

    【2hr】Molecular mechanisms driving respiratory syncytial virus assembly

    包量

    机译 驱动呼吸道合胞病毒组装的分子机制
    摘要：Respiratory syncytial virus is a single-stranded RNA virus in the Paramyxoviridae family that preferentially assembles and buds from the apical surface of polarized epithelial cells, forming filamentous structures that contain both viral proteins and the genomic RNA. Recent studies have described both viral and host factors that are involved in ribonucleoprotein assembly and trafficking of viral proteins to the cell surface. At the cell surface, viral proteins assemble into filaments that probably require interactions between viral proteins, host proteins and the cell membrane. Finally, a membrane scission event must occur to release the free virion. This article will review the recent literature describing the mechanisms that drive respiratory syncytial virus assembly and budding.
  • 12.

    【2hr】The RTX pore-forming toxin α-hemolysin of uropathogenic Escherichia coli: progress and perspectives

    包量

    机译 尿路致病性大肠杆菌的RTX成孔毒素α-溶血素的研究进展与展望
    摘要：Members of the RTX family of protein toxins are functionally conserved among an assortment of bacterial pathogens. By disrupting host cell integrity through their pore-forming and cytolytic activities, this class of toxins allows pathogens to effectively tamper with normal host cell processes, promoting pathogenesis. Here, we focus on the biology of RTX toxins by describing salient properties of a prototype member, α-hemolysin, which is of ten encoded by strains of uropathogenic Escherichia coli. It has long been appreciated that RTX toxins can have distinct effects on host cells aside from outright lysis. Recently, advances in modeling and analysis of host–pathogen interactions have led to novel findings concerning the consequences of pore formation during host–pathogen interactions. We discuss current progress on longstanding questions concerning cell specificity and pore formation, new areas of investigation that involve toxin-mediated perturbations of host cell signaling cascades and perspectives on the future of RTX toxin investigation.
  • 13.

    【2hr】Borrelia burgdorferi and tick proteins supporting pathogen persistence in the vector

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    机译 伯氏疏螺旋体和壁虱蛋白支持病原体在载体中的持久性
    摘要：Borrelia burgdorferi, a pathogen transmitted by Ixodes ticks, is responsible for a prevalent illness known as Lyme disease, and a vaccine for human use is unavailable. Recently, genome sequences of several B. burgdorferi strains and Ixodes scapularis ticks have been determined. In addition, remarkable progress has been made in developing molecular genetic tools to study the pathogen and vector, including their intricate relationship. These developments are helping unravel the mechanisms by which Lyme disease pathogens survive in a complex enzootic infection cycle. Notable discoveries have already contributed to understanding the spirochete gene regulation accounting for the temporal and spatial expression of B. burgdorferi genes during distinct phases of the lifecycle. A number of pathogen and vector gene products have also been identified that contribute to microbial virulence and/or persistence. These research directions will enrich our knowledge of vector-borne infections and contribute towards the development of preventative strategies against Lyme disease.
  • 14.

    【2hr】Emergence of multidrug-resistant, extensively drug-resistant and untreatable gonorrhea

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    机译 多重耐药，广泛耐药和无法治愈的淋病的出现
    摘要：The new superbug Neisseria gonorrhoeae has retained resistance to antimicrobials previously recommended for first-line treatment and has now demonstrated its capacity to develop resistance to the extended-spectrum cephalosporin, ceftriaxone, the last remaining option for first-line empiric treatment of gonorrhea. An era of untreatable gonorrhea may be approaching, which represents an exceedingly serious public health problem. Herein, we review the evolution, origin and spread of antimicrobial resistance and resistance determinants (with a focus on extended-spectrum cephalosporins) in N. gonorrhoeae, detail the current situation regarding verified treatment failures with extended-spectrum cephalosporins and future treatment options, and highlight essential actions to meet the large public health challenge that arises with the possible emergence of untreatable gonorrhea. Essential actions include: implementing action/response plans globally and nationally; enhancing surveillance of gonococcal antimicrobial resistance, treatment failures and antimicrobial use/misuse; and improving prevention, early diagnosis and treatment of gonorrhea. Novel treatment strategies, antimicrobials (or other compounds) and, ideally, a vaccine must be developed.
  • 15.

    【2hr】Mechanisms of antibiotic resistance in Burkholderia pseudomallei: implications for treatment of melioidosis

    包量

    机译 假伯克霍尔德氏菌对抗生素的耐药性机制：对类鼻oid病的治疗意义
    摘要：Burkholderia pseudomallei is the etiologic agent of melioidosis. This multifaceted disease is difficult to treat, resulting in high morbidity and mortality. Treatment of B. pseudomallei infections is lengthy and necessitates an intensive phase (parenteral ceftazidime, amoxicillin–clavulanic acid or meropenem) and an eradication phase (oral trimethoprim–sulfamethoxazole). The main resistance mechanisms affecting these antibiotics include enzymatic inactivation, target deletion and efflux from the cell, and are mediated by chromosomally encoded genes. Overproduction and mutations in the class A PenA β-lactamase cause ceftazidime and amoxicillin–clavulanic acid resistance. Deletion of the penicillin binding protein 3 results in ceftazidime resistance. BpeEF–OprC efflux pump expression causes trimethoprim and trimethoprim–sulfamethoxazole resistance. Although resistance is still relatively rare, therapeutic efficacies may be compromised by resistance emergence due to increased use of antibiotics in endemic regions. Novel agents and therapeutic strategies are being tested and, in some instances, show promise as anti-B. pseudomallei infectives.
  • 16.

    【2hr】Acquired inducible antimicrobial resistance in Gram-positive bacteria

    包量

    机译 在革兰氏阳性细菌中获得的诱导型抗菌素耐药性
    摘要：A major contributor to the emergence of antibiotic resistance in Gram-positive bacterial pathogens is the expansion of acquired, inducible genetic elements. Although acquired, inducible antibiotic resistance is not new, the interest in its molecular basis has been accelerated by the widening distribution and often ‘silent’ spread of the elements responsible, the diagnostic challenges of such resistance and the mounting limitations of available agents to treat Gram-positive infections. Acquired, inducible antibiotic resistance elements belong to the accessory genome of a species and are horizontally acquired by transformation/recombination or through the transfer of mobile DNA elements. The two key, but mechanistically very different, induction mechanisms are: ribosome-sensed induction, characteristic of the macrolide–lincosamide–streptogramin B antibiotics and tetracycline resistance, leading to ribosomal modifications or efflux pump activation; and resistance by cell surface-associated sensing of β-lactams (e.g., oxacillin), glycopeptides (e.g., vancomycin) and the polypeptide bacitracin, leading to drug inactivation or resistance due to cell wall alterations.
  • 17.

    【2hr】Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action

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    机译 SQ109的发现和开发：具有新型作用机理的新型抗结核药
    摘要：Existing drugs have limited efficacy against the rising threat of drug-resistant TB, have significant side effects, and must be given in combinations of four to six drugs for at least 6 months for drug-sensitive TB and up to 24 months for drug-resistant TB. The long treatment duration has led to increased patient noncompliance with therapy. This, in turn, drives the development of additional drug resistance in a spiral that has resulted in some forms of TB being currently untreatable by existing drugs. New antitubercular drugs in development, particularly those with mechanisms of action that are different from existing first- and second-line TB drugs, are anticipated to be effective against both drug-sensitive and drug-resistant TB. SQ109 is a new TB drug candidate with a novel mechanism of action that was safe and well tolerated in Phase I and early Phase II clinical trials. We describe herein the identification, development and characterization of SQ109 as a promising new antitubercular drug.
  • 18.

    【2hr】Anaplasma phagocytophilum: deceptively simple or simply deceptive?

    包量

    机译 吞噬细胞无浆膜：看似简单还是简单的欺骗？
    摘要：Anaplasma phagocytophilum is an obligate intracellular rickettsial pathogen transmitted by ixodid ticks. This bacterium colonizes myeloid and nonmyeloid cells and causes human granulocytic anaplasmosis – an important immunopathological vector-borne disease in the USA, Europe and Asia. Recent studies uncovered novel insights into the mechanisms of A. phagocytophilum pathogenesis and immunity. Here, we provide an overview of the underlying events by which the immune system responds to A. phagocytophilum infection, how this pathogen counteracts host immunity and the contribution of the tick vector for microbial transmission. We also discuss current scientific gaps in the knowledge of A. phagocytophilum biology for the purpose of exchanging research perspectives.
  • 19.

    【2hr】Invasive fungal infections in solid organ transplant recipients

    包量

    机译 实体器官移植受者的侵袭性真菌感染
    摘要：Invasive fungal infections are a major problem in solid organ transplant (SOT) recipients. Overall, the most common fungal infection in SOT is candidiasis, followed by aspergillosis and cryptococcosis, except in lung transplant recipients, where aspergillosis is most common. Development of invasive disease hinges on the interplay between host factors (e.g., integrity of anatomical barriers, innate and acquired immunity) and fungal factors (e.g., exposure, virulence and resistance to prophylaxis). In this article, we describe the epidemiology and clinical features of the most common fungal infections in organ transplantation. Within this context, we review recent advances in diagnostic modalities and antifungal chemotherapy, and their impact on evolving prophylaxis and treatment paradigms.
  • 20.

    【2hr】Development of humanized mouse models to study human malaria parasite infection

    包量

    机译 人源化小鼠模型的研究，以研究人类疟疾寄生虫感染
    摘要：Malaria is a disease caused by infection with Plasmodium parasites that are transmitted by mosquito bite. Five different species of Plasmodium infect humans with severe disease, but human malaria is primarily caused by Plasmodium falciparum. The burden of malaria on the developing world is enormous, and a fully protective vaccine is still elusive. One of the biggest challenges in the quest for the development of new antimalarial drugs and vaccines is the lack of accessible animal models to study P. falciparum infection because the parasite is restricted to the great apes and human hosts. Here, we review the current state of research in this field and provide an outlook of the development of humanized small animal models to study P. falciparum infection that will accelerate fundamental research into human parasite biology and could accelerate drug and vaccine design in the future.
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