Bacterial biofilms are a major threat to human health, causing persistent infections that lead to millions of fatalities worldwide every year. Biofilms also cause billions of dollars of damage annually by interfering with industrial processes. Recently, cationic pillararenes were found to be potent inhibitors of biofilm formation in Gram-positive bacteria. To identify the structural features of pillararenes that result in antibiofilm activity, we evaluated the activity of 16 cationic pillar[5]arene derivatives including that of the first cationic water-soluble pillar[5]arene-based rotaxane. Twelve of the derivatives were potent inhibitors of biofilm formation by Gram-positive pathogens. Structure activity analyses of our pillararene derivatives indicated that positively charged head groups are critical for the observed antibiofilm activity. Although certain changes in the lipophilicity of the substituents on the positively charged head groups are tolerated, dramatic elevation in the hydrophobicity of the substituents or an increase in steric bulk on these positive charges abolishes the antibiofilm activity. An increase in the overall positive charge from 10 to 20 did not affect the activity significantly, but pillararenes with 5 positive charges and 5 long alkyl chains had reduced activity. Surprisingly, the cavity of the pillar[n]arene is not essential for the observed activity, although the macrocyclic structure of the pillar[n]arene core, which facilitates the clustering of the positive charges, appears important. Interestingly, the compounds found to be efficient inhibitors of biofilm formation were nonhemolytic at concentrations that are ∼100-fold of their MBIC50 (the minimal concentration of a compound at which at least 50% inhibition of biofilm formation was observed compared to untreated cells). The structure-activity relationship guidelines established here pave the way for a rational design of potent cationic pillar[n]arene-based antibiofilm agents.

The International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia were published in 2017 whilst the American guidelines for Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia were launched in 2016 by the Infectious Diseases Society of America/ATS. Both guidelines made updated recommendations based on the most recent evidence sharing not only some parallelisms but also important conceptual differences.
Contemporary therapy for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) emphasizes the importance of prompt and appropriate antimicrobial therapy. There is an implicit risk, when appropriate means broad spectrum, that liberal use of antimicrobial combinations will encourage the emergence of multidrug resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant bacteria (PDR) and generate untreatable infections, including carbapenemase resistant infections.
American and European guidelines have many areas of common agreement such as limiting antibiotic duration. Both guidelines were in favour of a close clinical assessment. Neither recommended a regular use of biomarkers but only in specific circumstances such as dealing with MDR and treatment failure. Risk factor prediction for MDR differed and whilst American guidelines focus on organ failure, the European ones did it in local ecology and septic shock.

GSK2140944 is a novel bacterial type II topoisomerase inhibitor in development for the treatment of conventional and biothreat pathogens, including Gram-positive pathogens and methicillin-resistant Staphylococcus aureus. This quality control study was performed to establish ranges for selected control strains: S. aureus ATCC 29213 and ATCC 25923, Escherichia coli ATCC 25922, Haemophilus influenzae ATCC 49247, and Streptococcus pneumoniae ATCC 49619. The control ranges will be crucial for the accurate evaluation of GSK2140944 potency as it progresses through clinical trial development.

Consensus-sequence engineering has generated protein variants with enhanced stability, and sometimes, with modulated biological function. Consensus mutations are often interpreted as the introduction of ancestral amino acid residues. However, the precise relationship between consensus engineering and ancestral protein resurrection is not fully understood. Here, we report the properties of proteins encoded by consensus sequences derived from a multiple sequence alignment of extant, class A β-lactamases, as compared with the properties of ancient Precambrian β-lactamases resurrected in the laboratory. These comparisons considered primary sequence, secondary, and tertiary structure, as well as stability and catalysis against different antibiotics. Out of the three consensus variants generated, one could not be expressed and purified (likely due to misfolding and/or low stability) and only one displayed substantial stability having substrate promiscuity, although to a lower extent than ancient β-lactamases. These results: (i) highlight the phenotypic differences between consensus variants and laboratory resurrections of ancestral proteins; (ii) question interpretations of consensus proteins as phenotypic proxies of ancestral proteins; and (iii) support the notion that ancient proteins provide a robust approach toward the preparation of protein variants having large numbers of mutational changes while possessing unique biomolecular properties.

暂无摘要。

GSK2251052 is a boron-containing antimicrobial agent in clinical development for the treatment of serious Gram-negative bacterial infections. These GSK2251052 quality control (QC) studies were performed to establish ranges for control strains (broth microdilution [BMD] MIC and disk diffusion zones) as follows: Pseudomonas aeruginosa ATCC 27853 (2-8 μg/mL and 15-24 mm), Escherichia coli ATCC 25922 (0.5-2 μg/mL and 23-30 mm), Haemophilus influenzae ATCC 49247 (0.25-1 μg/mL and 22-31 mm), Streptococcus pneumoniae ATCC 49619 (0.25-1 μg/mL and 19-28 mm), Bacteroides fragilis ATCC 25285 (1-4 μg/mL [BMD] and 1-4 μg/mL [agar dilution]), and Bacteroides thetaiotaomicron ATCC 29741 (1-8 μg/mL [BMD] and 2-8 μg/mL [agar dilution]). These ranges, approved by Clinical and Laboratory Standards Institute, will be crucial in accurately evaluating GSK2251052 in vitro potency.

暂无摘要。

BACKGROUND: Two detailed checklists were developed, based on published infection control guidelines, for daily use by infection control practitioners in departments and operating rooms.
OBJECTIVE: To assess the impact of the checklists on nosocomial infection rates in three hospitals over the course of one year.
METHODS: The checklists included 20 subheadings (± 150 items). Project nurses conducted rounds in the study (but not control) departments; during each round, the nurses selected 15-20 items for observation, marked the checklists according to appropriateness of observed behaviour and provided on-the-spot corrective education. Rates of adherence to the checklist, antibiotic use, number of obtained and positive cultures, and positive staff hand and patient environment cultures were reported monthly as a report card to relevant personnel and administrators. The rate of nosocomial infections was determined in the first and last months.
RESULTS: The baseline nosocomial infection rate was similar in the study and control departments: 37/345 (11%) and 26/270 (10%) respectively. In the last month, the rate in the study department decreased to 16/383 (4%) (P<0.01); in the control it decreased insignificantly to 21/248 (8%) (not significant). No significant trends were detected in the number of obtained cultures, positive cultures, or antibiotic use. Adherence to guidelines ranged from 75% to 94% between the hospitals (P<0.001): the overall rate increased from 80% to 91% (P<0.01).
CONCLUSIONS: The use of checklists during the conduct of infection control rounds, combined with monthly reports, was associated with a significant decrease in nosocomial infections in study departments.

In our previous study, we reported that urechistachykinin I (U I) and II (U II) exerted antimicrobial effects. To find out how the tachykinin consensus sequence of the urechistachykinin peptide family affects its antimicrobial activity, analogues substituting the amino acid residues phenylalanine (Phe-6; Anal 1), glycine (Gly-8; Anal 2), and arginine (Arg-10; Anal 3) of U II to alanine (Ala) were designed. Subsequently, the antimicrobial activity was shown on the order of Anal 3>U II=Anal 2>Anal 1, and this activity pattern was correlated with membrane studies such as propidium iodide (PI) influx and fluorescein isothiocyanate dextran (FD) leakage assay. These results suggest that the antimicrobial activity is related to the hydrophobicity values of the peptides. In regards to the activity of U II, it is determined that the hydrophobic Phe-6 plays a more critical role than Gly-8 or Arg-10.

BACKGROUND: Hospital-associated pneumonia (HAP) remains an important cause of morbidity and mortality despite advances in antimicrobial therapy. Many aspects of the treatment of HAP caused by multi-resistant Gram-positive microorganisms have been extensively studied, but controversial issues remain.
OBJECTIVE: The aim of this GISIG (Gruppo Italiano di Studio sulle Infezioni Gravi) working group - a panel of multidisciplinary experts - was to define recommendations for some controversial issues using an evidence-based and analytical approach. The controversial issues were: (1) Is combination antibiotic therapy or monotherapy more effective in the treatment of HAP? (2) What role do pharmacokinetic/pharmacodynamic antibiotic features have as a guide in the selection of treatment for HAP? (3) Is a de-escalation approach for the management of HAP effective? An analysis of the studies published up until April 2009 is presented and discussed in detail.
METHODS: A systematic literature search using PubMed, MEDLINE, and EMBASE databases and the Cochrane Library was performed. A matrix was created to extract evidence from original studies using the CONSORT method to evaluate randomized clinical trials and the Newcastle-Ottawa Quality Assessment Scale for case-control studies, longitudinal cohorts, and retrospective studies. The GRADE method for grading quality of evidence was applied.