抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

J. Appl. Cryst.の発刊に際して

Multicellular organisms live, by and large, harmoniously with microbes. The cornea of the eye of an animal is almost always free of signs of infection. The insect flourishes without lymphocytes or antibodies. A plant seed germinates successfully in the midst of soil microbes. How is this accomplished? Both animals and plants possess potent, broad-spectrum antimicrobial peptides, which they use to fend off a wide range of microbes, including bacteria, fungi, viruses and protozoa. What sorts of molecules are they? How are they employed by animals in their defence? As our need for new antibiotics becomes more pressing, could we design anti-infective drugs based on the design principles these molecules teach us?

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Antimicrobial peptides of multicellular organisms

Peptides or proteins convert under some conditions from their soluble forms into highly ordered fibrillar aggregates. Such transitions can give rise to pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we identify the diseases known to be associated with formation of fibrillar aggregates and the specific peptides and proteins involved in each case. We describe, in addition, that living organisms can take advantage of the inherent ability of proteins to form such structures to generate novel and diverse biological functions. We review recent advances toward the elucidation of the structures of amyloid fibrils and the mechanisms of their formation at a molecular level. Finally, we discuss the relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate and describe some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior.

/pdf/protein-misfolding-functional-amyloid-and-human-disease-2w386pwb7k.pdf

Protein Misfolding, Functional Amyloid, and Human Disease

Few microorganisms are as versatile as Escherichia coli. An important member of the normal intestinal microflora of humans and other mammals, E. coli has also been widely exploited as a cloning host in recombinant DNA technology. But E. coli is more than just a laboratory workhorse or harmless intestinal inhabitant; it can also be a highly versatile, and frequently deadly, pathogen. Several different E. coli strains cause diverse intestinal and extraintestinal diseases by means of virulence factors that affect a wide range of cellular processes.

Pathogenic Escherichia coli

The present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in combination with a drug against a disease involving gram-positive bacteria.

Ring-fused thiazolino 2-pyridones, methods for preparation thereof and their use in the treatment and/or prevention of a disease involving gram-positive bacteria

Due to bacterial resistance, there is a constant struggle to get new treatments for bacterial diseases. A wide range of pathogenic gram-negative bacteria such as E. coli, K. pneumonia and Y. Pestis assembles hair-like adhesive protein filaments called pili on their surfaces. These organelles mediate attachment to the host-cell during microbial invasion. The stabilization and transportation of pilus subunits through the periplasmic compartment by a periplasmic chaperone is crucial in pilus assembly. Inhibition of the chaperone/subunit complex, thus preventing pilus assembly, appears to be a good target for development of a new antibacterial drug.

Design, Synthesis and Biological Evaluation of Pilicides: Inhibitors of Pilus Assembly in Pathogenic Bacteria

The antimicrobial triclosan is used in a wide range of consumer products ranging from toothpaste, cleansers, socks, and baby toys. A bacteriostatic inhibitor of fatty acid synthesis, triclosan is extremely stable and accumulates in the environment. Approximately 75% of adults in the US have detectable levels of the compound in their urine, with a sizeable fraction of individuals (>10%) having urine concentrations equal to or greater than the minimal inhibitory concentration for Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA). Previous work has identified connections between defects in fatty acid synthesis and accumulation of the alarmone guanosine tetraphosphate (ppGpp), which has been repeatedly associated with antibiotic tolerance and persistence. Based on these data, we hypothesized that triclosan exposure may inadvertently drive bacteria into a state in which they are able to tolerate normally lethal concentrations of antibiotics. Here we report that clinically relevant concentrations of triclosan increased E. coli and MRSA tolerance to bactericidal antibiotics as much as 10,000 fold in vitro and reduced antibiotic efficacy up to 100-fold in a mouse urinary tract infection model. Genetic analysis indicated that triclosan-mediated antibiotic tolerance requires ppGpp synthesis, but is independent of growth. These data highlight an unexpected and certainly unintended consequence of adding high concentrations of antimicrobials in consumer products, supporting an urgent need to reevaluate the costs and benefits of the prophylactic use of triclosan and other bacteriostatic compounds. Importance Added as a prophylactic to a wide range of consumer products, the fatty acid synthesis inhibitor triclosan accumulates to high levels in humans and the environment. Based on links between defects in fatty acid synthesis and accumulation of the alarmone ppGpp, we hypothesized that triclosan would render cells tolerant to bactericidal compounds due to ppGpp-mediated inhibition of biosynthetic capacity. Our data indicate that clinically relevant concentrations of triclosan induces higher tolerance of E. coli and methicillin resistant S. aureus (MRSA) to a panel of bactericidal antibiotics up to 10,000-fold. In a urinary tract infection model, mice exposed to triclosan exhibited bacterial loads ~100-fold higher in the bladder than control animals following ciprofloxacin challenge. These findings highlight an unexpected consequence of antimicrobials in consumer products and support an urgent need to reevaluate the costs and benefits of the prophylactic use of triclosan and other bacteriostatic compounds.

/pdf/the-commercial-antimicrobial-triclosan-induces-high-levels-50w52z8lad.pdf

The commercial antimicrobial triclosan induces high levels of antibiotic tolerance in vitro and reduces antibiotic efficacy up to 100-fold in vivo

/pdf/escherichia-coli-lipopolysaccharide-and-type-1-piliated-2jwh1vub74.pdf

Escherichia coli Lipopolysaccharide and Type 1 Piliated Activation of Bladder Epithelial Cells by CD14- and Toll-Like Receptor-Dependent

Plusieurs pathogenes Gram negatif assemblent des structures adhesives sur leur surface, ce qui leur permet de coloniser des tissus hotes et de provoquer des maladies. L'invention concerne des nouvelles compositions qui inhibent ou empechent la formation d'un complexe sous-unitaire/pilus chaperon. L'interaction avec la fonction du pilus chaperon affecte de maniere negative le mecanisme d'action de ce chaperon/huissier, lequel est un mecanisme moleculaire permettant aux bacteries Gram negatif d'assembler des structures de pilus adhesives, et donc empeche ou inhibe l'assemblage de pilus. L'invention concerne egalement des procedes de traitement ou de prevention de maladies provoquees par des bacteries formatrices de pilus et adherant aux tissus, consistant a inhiber la fonction de ces pilus chaperons. L'invention concerne encore des preparations pharmaceutiques pouvant inhiber ou empecher la formation d'un complexe sous-unitaire/pilus chaperon, des procedes de synthese des composes d'acides amines N-substitues, des composes utiles pour cette synthese, et notamment des nouveaux composes de liaison fluores, ainsi que des procedes de synthese. L'invention concerne enfin des procedes d'utilisation de ces composes de liaison fluores dans la synthese en phase solide de composes d'acides amines N-substitues.

Scott J. Hultgren

Papers

Ring-fused thiazolino 2-pyridones, methods for preparation thereof and their use in the treatment and/or prevention of a disease involving gram-positive bacteria

Design, Synthesis and Biological Evaluation of Pilicides: Inhibitors of Pilus Assembly in Pathogenic Bacteria

The commercial antimicrobial triclosan induces high levels of antibiotic tolerance in vitro and reduces antibiotic efficacy up to 100-fold in vivo

Escherichia coli Lipopolysaccharide and Type 1 Piliated Activation of Bladder Epithelial Cells by CD14- and Toll-Like Receptor-Dependent

Composes diriges contre la biogenese et l'activite du pilus de bacteries pathogenes, et procedes et compositions de synthese destines a ces composes