Synergistic Anti-Candida Activity of Bengazole A in the Presence of Bengamide A †.

Bengazoles A⁻G from the marine sponge Jaspis sp. exhibit potent in vitro antifungal activity against Candida spp. and other pathogenic fungi. The mechanism of action (MOA) of bengazole A was explored in Candida albicans under both liquid culture and surface culture on Mueller-Hinton agar. Pronounced dose-dependent synergistic antifungal activity was observed with bengazole A in the presence of bengamide A, which is also a natural product from Jaspis sp. The MOA of bengazole A was further explored by monitoring the sterol composition of C. albicans in the presence of sub-lethal concentrations of bengazole A. The GCMS of solvent extracts prepared from liquid cultures of C. albicans in the presence of clotrimazole-a clinically approved azole antifungal drug that suppresses ergosterol biosynthesis by the inhibition of 14α-demethylase-showed reduced cellular ergosterol content and increased concentrations of lanosterol and 24-methylenedihydrolanosterol (a shunt metabolite of ergosterol biosynthesis). No change in relative sterol composition was observed when C. albicans was cultured with bengazole A. These results eliminate an azole-like MOA for the bengazoles, and suggest that another as-yet unidentified mechanism is operative

Biophysical Approaches Facilitate Computational Drug Discovery for ATP-Binding Cassette Proteins

Although membrane proteins represent most therapeutically relevant drug targets, the availability of atomic resolution structures for this class of proteins has been limited. Structural characterization has been hampered by the biophysical nature of these polytopic transporters, receptors, and channels, and recent innovations to in vitro techniques aim to mitigate these challenges. One such class of membrane proteins, the ATP-binding cassette (ABC) superfamily, are broadly expressed throughout the human body, required for normal physiology and disease-causing when mutated, yet lacks sufficient structural representation in the Protein Data Bank. However, recent improvements to biophysical techniques (e.g., cryo-electron microscopy) have allowed for previously “hard-to-study” ABC proteins to be characterized at high resolution, providing insight into molecular mechanisms-of-action as well as revealing novel druggable sites for therapy design. These new advances provide ample opportunity for computational methods (e.g., virtual screening, molecular dynamics simulations, and structure-based drug design) to catalyze the discovery of novel small molecule therapeutics that can be easily translated from computer to bench and subsequently to the patient’s bedside. In this review, we explore the utility of recent advances in biophysical methods coupled with well-established in silico techniques towards drug development for diseases caused by dysfunctional ABC proteins

Eine empirische Analyse der Bedeutung der strategischen Erfolgsfaktoren von Hidden Champions für mittelständische Unternehmen

Die Implementierung strategischer Erfolgsfaktoren rückt zunehmend in den Fokus kleiner und mittelständischer Unternehmen. Vor dem Hintergrund des überdurchschnittlichen Erfolgs sogenannter Hidden Champions (HC) stellt sich unter einer praxisorientierten Perspektive die Frage, welche Bedeutung mittelständische Unternehmen grundsätzlich den von Hermann Simon identifizierten Erfolgsprinzipien für HC für den Unternehmenserfolg zumessen. Die empirische Studie analysierte dazu die Bedeutung dieser Erfolgsfaktoren für mittelständische Unternehmen und untersuchte, ob Bedeutungsunterschiede zwischen erfolgreichen und weniger erfolgreichen Unternehmen der Stichprobe existieren. Im Rahmen einer explorativen, multivariaten Datenanalyse konnten außerdem zwei Cluster, die „Internationalen Innovatoren“ und die „Nationalen Traditionalisten“, im Datensatz identifiziert werden, die sich hinreichend in der Bedeutungszumessung der Erfolgsfaktoren voneinander unterschieden.The implementation of strategic success factors is increasingly gaining the attention of small and medium-sized enterprises. In light of the above-average success of so-called hidden champions (HC), the question arises which importance medium-sized companies in general attach to the success principles for HC identified by Hermann Simon. This empirical study analyzed the importance of these success factors for small and medium-sized enterprises and investigated whether differences in relevance exist between successful and less successful companies in the sample. An explorative, multivariate data analysis also identified two clusters in the data set, the "international innovators" and the "national traditionalists", which differed sufficiently from each other in the measurement of the importance of these success factors