Discovery of antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3 H)-one

© 2015 American Chemical Society. In the face of the clinical challenge posed by resistant bacteria, the present needs for novel classes of antibiotics are genuine. In silico docking and screening, followed by chemical synthesis of a library of quinazolinones, led to the discovery of (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one (compound 2) as an antibiotic effective in vivo against methicillin-resistant Staphylococcus aureus (MRSA). This antibiotic impairs cell-wall biosynthesis as documented by functional assays, showing binding of 2 to penicillin-binding protein (PBP) 2a. We document that the antibiotic also inhibits PBP1 of S. aureus, indicating a broad targeting of structurally similar PBPs by this antibiotic. This class of antibiotics holds promise in fighting MRSA infections.Peer Reviewe

Cigarette smoke causes acute airways disease and exacerbates chronic obstructive lung disease in neonatal mice.

Epidemiological evidence demonstrates a strong link between postnatal cigarette smoke (CS)-exposure and increased respiratory morbidity in young children. However, how CS induces early onset airways disease in young children and how it interacts with endogenous risk factors remains poorly understood. We, therefore exposed 10 day old neonatal wild-type and βENaC-transgenic mice with cystic fibrosis like lung disease to CS for 4 days. Neonatal wild-type mice exposed to CS demonstrated increased numbers of macrophages and neutrophils in the BALF which was accompanied by increased levels of Mmp12 and Cxcl1. BALF from βENaC-transgenic mice contained greater numbers of macrophages which did not increase following acute CS-exposure, however there was significant increase in airway neutrophilia compared to filtered air transgenic and CS-exposed wild-type controls. Interestingly, wild-type and βENaC-transgenic mice demonstrated epithelial airway and vascular remodeling following CS-exposure. Morphometric analysis of lung sections revealed that CS-exposure caused increased mucus accumulation in the airway lumen of neonatal βENaC-transgenic mice compared to wild-type controls, which was accompanied by an increase in the number of goblet cells and Muc5ac upregulation. We conclude that short-term CS exposure i) induces acute airways disease with airway epithelial and vascular remodeling in neonatal wild-type mice; and ii) exacerbates airway inflammation, mucus hypersecretion and mucus plugging in neonatal βENaC-transgenic mice with chronic lung disease. Our results in neonatal mice suggest that young children may be highly susceptible to develop airways disease in response to tobacco smoke exposure and that adverse effects may be aggravated in children with underlying chronic lung diseases

Building a climate of trust during organizational change: The mediating role of justice perceptions and emotion

Over the years, research has shown that, although there are various factors which contribute to failed change, one of the key reasons people resist change is due to the inability of leaders to convince employees to support change and to commit the energy and effort necessary to implement it. Senior management can ensure an organization is change-ready by developing and maintaining a supportive culture and climate that positively influence the emotional health and welfare of employees. Despite the obvious importance of leadership to change efforts, little previous research has investigated, holistically and in the context of major change, the relationship between senior management actions and employee responses. Furthermore, the change literature largely ignores the role that emotions play in employee responses to change initiatives. This chapter addresses both areas, and develops a model of organizational change from a justice and emotions perspective, which depicts employees’ justice perceptions related to senior executives as affecting trust directly and indirectly, through associated emotional responses