The development of antimicrobial drugs, and particularly of antibiotics, has played a considerable role in substantially reducing the morbidity and mortality rates ofmany infectious diseases. However, thefact that bacteria can develop resistance to antibiotics has produced a situation where antimicrobial agents are losing their effectiveness because of the spread and persistence of drug-resistant organisms. To combat this, more and more antibiotics with increased therapeutic and prophylactic action will need to be developed. This article is concerned with antibiotic resistance in bacteria which are pathogenic to man and animals. The historical background is given, as well as some information on the present situation and trends of antibiotic resistance to certain bacteria in different parts of the world. Considerable concern is raised over the use of antibiotics in man and animals. It is stated that antibiotic resistance in human pathogens is widely attributed to the "misuse" of antibiotics for treatment and prophylaxis in man and to the administration of antibiotics to animals for a variety of purposes (growth promotion, prophylaxis, or therapy), leading to the accumulation of resistant bacteria in their flora. Factors favouring the development of resistance are discussed.
The clathrin adaptors AP-1 and AP-2 bind cargo proteins via two types of motifs: tyrosine-based Yxx phi and dileucine-based [DE]XXXL[LI]. Although it is well established that Yxx phi motifs bind to the mu subunits of AP-1 or AP-2, dileucine motifs have been reported to bind to either the mu or beta subunits of these adaptors as well as the gamma/sigma1 hemicomplex of AP-1. To clarify this controversy, the various subunits of AP-1 and AP-2 were expressed individually and in hemicomplex form in insect cells, and they were used in glutathione S-transferase pull-down assays to determine their binding properties. We report that the gamma/sigma1 or alpha/sigma2 hemicomplexes bound the dileucine-based motifs of several proteins quite strongly, whereas binding by the beta1/mu1 and beta2/mu2 hemicomplexes, and the individual beta or mu subunits, was extremely weak or undetectable. The gamma/sigma1 and alpha/sigma2 hemicomplexes displayed substantial differences in their preference for particular dileucine-based motifs. Most strikingly, an aspartate at position -4 compromised binding to the gamma/sigma1 hemicomplex, whereas minimally affecting binding to alpha/sigma2. There was an excellent correlation between binding to the alpha/sigma2 hemicomplex and in vivo internalization mediated by the dileucine-based sorting signals. These findings provide new insights into the trafficking mechanisms of D/EXXXL[LI]-mediated sorting signals.
Increasing antimicrobial resistance and medical device-related infections have led to a renewed interest in phage therapy as an alternative or adjunct to conventional antimicrobials. Expanded access and compassionate use cases have risen exponentially but have varied widely in approach, methodology, clinical situations in which phage therapy might be considered, dosing, route of administration, and outcomes. Large gaps in knowledge contribute to a heterogeneity in approach and lack of clear consensus in many important clinical areas. Here, the Antibacterial Resistance Leadership Group (ARLG) has convened a panel of experts in phage therapy, clinical microbiology, infectious diseases, and pharmacology, who worked with regulatory experts and a funding agency to identify questions based on a clinical framework and divided them into three themes: potential clinical situations in which phage therapy might be considered, and laboratory testing and pharmacokinetic considerations. Suggestions are provided as answers to a series of questions intended to inform clinicians considering experimental phage therapy for patients in their clinical practices.
The low density lipoprotein (LDL) receptor-related protein 1B (LRP1B) is a newly identified member of the LDL receptor family that shares high homology with the LDL receptor-related protein (LRP). LRP1B was originally described as a putative tumor suppressor in lung cancer cells; however, its expression profile in several regions of adult human brain suggests it may have additional functions in the central nervous system. Since LRP1B has overlapping ligand binding properties with LRP, we investigated whether LRP1B, like LRP, could interact with the -amyloid precursor protein (APP) and modulate its processing to amyloid- peptides (As). Using an LRP1B minireceptor (mLRP1B4) generated to study the trafficking of LRP1B, we found that mLRP1B4 and APP form an immunoprecipitable complex. Furthermore mLRP1B4 bound and facilitated the degradation of a soluble isoform of APP containing a Kunitz proteinase inhibitor domain but not soluble APP lacking a Kunitz proteinase inhibitor domain. A functional consequence of mLRP1B4 expression was a significant accumulation of APP at the cell surface, which is likely related to the slow endocytosis rate of LRP1B. More importantly, mLRP1B4-expressing cells that accumulated cell surface APP produced less A and secreted more soluble APP. These findings reveal that LRP1B is a novel binding partner of APP that functions to decrease APP processing to A. Consequently LRP1B expression could function to protect against the pathogenesis of Alzheimer's disease. Alzheimer's disease (AD)1 is characterized by the accumulation of neuritic plaques and neurofibrillary tangles in the brain.A major component of plaques is fibrillar aggregates of amyloid- peptides (As), which are derived from the processing of a ϳ120-kDa transmembrane protein known as -amyloid precursor protein (APP) (1). APP, which exists in three main isoforms (APP695, APP751, and APP770), can undergo two post-translational processing pathways. In the amyloidogenic pathway, APP is cleaved first at a -secretase site by the enzyme, -site APP-cleaving enzyme, and subsequently by a ␥-secretase within its intramembrane region to release the A peptide (2). In the non-amyloidogenic pathway, APP is processed by an ␣-secretase that clips within the A region, resulting in the release of a soluble APP fragment (sAPP␣), which may function in blood coagulation and neurite outgrowth (3, 4). Several studies have shown that reducing APP endocytosis, either by biochemical methods or mutation of residues within its tail, results in a marked increase in sAPP␣ secretion and decrease in A production, suggesting that these pathways are mutually exclusive (5, 6).In addition to modification by secretases, APP trafficking and processing are also regulated by other proteins, one of which is the low density lipoprotein (LDL) receptor-related protein (LRP). LRP is a multifunctional endocytic receptor that is highly expressed in the brain (7). LRP can internalize APP from the cell surface via extracellular interactions mediated by the Kunitz protein...
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