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Background Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is increasing worldwide, with Mycobacterium avium complex (MAC) and Mycobacterium abscessus as the predominant pathogens. Current treatments are poorly tolerated and modestly effective, highlighting the need for new treatments. SPR719, the active moiety of the benzimidazole prodrug SPR720, inhibits the ATPase subunits of DNA gyrase B, a target not exploited by current antibiotics, and therefore, no cross-resistance is expected with standard-of-care (SOC) agents. Objectives To evaluate the in vitro activity of SPR719 against MAC and M. abscessus clinical isolates, including those resistant to SOC agents, and in vivo efficacy of SPR720 in murine non-tuberculous mycobacteria (NTM) pulmonary infection models. Methods NTM isolates were tested for susceptibility to SPR719. Chronic C3HeB/FeJ and severe combined immunodeficient murine models of pulmonary infection were used to assess efficacy of SPR720 against MAC and M. abscessus , respectively. Results SPR719 was active against MAC (MIC90, 2 mg/L) and M. abscessus (MIC90, 4 mg/L) clinical isolates. Efficacy of SPR720 was demonstrated against MAC pulmonary infection, both as a monotherapy and in combination with SOC agents. SPR720 monotherapy exhibited dose-dependent reduction in bacterial burden, with the largest reduction observed when combined with clarithromycin and ethambutol. Efficacy of SPR720 was also demonstrated against M. abscessus pulmonary infection where monotherapy exhibited a dose-dependent reduction in bacterial burden with further reductions detected when combined with SOC agents. Conclusions In vitro activity of SPR720 against common NTM pathogens and efficacy in murine infections warrant the continued clinical evaluation of SPR720 as a new oral option for the treatment of NTM-PD. [ABSTRACT FROM AUTHOR]

Describes the results of a survey of undergraduate students enrolled in courses that incorporate Web-based modules that assessed their satisfaction with learning in a digital instructional environment, with the goal of identifying learners' temperaments as possible predictors of satisfaction. Discusses use of the Keirsey Temperament Sorter II. (Author/LRW)

An approach to bicyclo (5,3,0) ring systems is reported, based on cyclopropanation of functionalized cyclobutenes.

Research was conducted to examine techniques in circumventing a difficult coupling in the solid-phase synthesis of cyclosporine analogues. The successful syntheses of (MeSer1)Cs, (MeThr1)-Cs and (MeLeu(3-OH)1)Cs, analogues of Cs with a beta-hydroxy amino acid in the 1-position were performed using three procedures that overcome the difficult 11-1 coupling. The combination of solid-phase and solution methods has accelerated the production of Cs analogues from months using only solution-phase techniques to a matter of days.

DNA ligases are indispensable enzymes playing a critical role in DNA replication, recombination, and repair in all living organisms. Bacterial NAD+-dependent DNA ligase (LigA) was evaluated for its potential as a broad-spectrum antibacterial target. A novel class of substituted adenosine analogs was discovered by target-based high-throughput screening (HTS), and these compounds were optimized to render them more effective and selective inhibitors of LigA. The adenosine analogs inhibited the LigA activities of Escherichia coli, Haemophilus influenzae, Mycoplasma pneumoniae, Streptococcus pneumoniae, and Staphylococcus aureus, with inhibitory activities in the nanomolar range. They were selective for bacterial NAD+-dependent DNA ligases, showing no inhibitory activity against ATP-dependent human DNA ligase 1 or bacteriophage T4 ligase. Enzyme kinetic measurements demonstrated that the compounds bind competitively with NAD+. X-ray crystallography demonstrated that the adenosine analogs bind in the AMP-binding pocket of the LigA adenylation domain. Antibacterial activity was observed against pathogenic Gram-positive and atypical bacteria, such as S. aureus, S. pneumoniae, Streptococcus pyogenes, and M. pneumoniae, as well as against Gram-negative pathogens, such as H. influenzae and Moraxella catarrhalis. The mode of action was verified using recombinant strains with altered LigA expression, an Okazaki fragment accumulation assay, and the isolation of resistant strains with ligA mutations. In vivo efficacy was demonstrated in a murine S. aureus thigh infection model and a murine S. pneumoniae lung infection model. Treatment with the adenosine analogs reduced the bacterial burden (expressed in CFU) in the corresponding infected organ tissue as much as 1,000-fold, thus validating LigA as a target for antibacterial therapy.

The Web can provide a quick and easy way to access health information, especially for elderly users. However, these health information sites need to be accessible and usable. In spite of legislation and clear guidelines, there continues to be issues of poor accessibility and usability. Because of an aging population and the likelihood of being more susceptible to age-related impairments such as restricted vision and mobility, the severity of this problem continues to grow. This article presents the results of an exploratory study aimed at assessing the accessibility and usability of three health information Web sites for elderly novice users. The results from the study show that certain aspects of these Web sites make it difficult for elderly people to use them, especially if the users have impairments. Problematic areas are highlighted regarding usability and accessibility, and recommendations are made based on the findings.