Albicidin is a potent DNA gyrase inhibitor produced by the sugarcane pathogenic bacterium Xanthomonas albilineans. Here we report the elucidation of the hitherto unknown structure of albicidin, revealing a unique polyaromatic oligopeptide mainly composed of p-aminobenzoic acids. In vitro studies provide further insights into the biosynthetic machinery of albicidin. These findings will enable structural investigations on the inhibition mechanism of albicidin and its assessment as a highly effective antibacterial drug.
Covering: up to mid-2014 Over the last several decades, the number of pharmacologically active natural products has significantly increased and several natural product families have taken shape. This review highlights the family of tetronate and spirotetronate compounds, which show a vast structural and functional diversity. The rapid growth of this group has created the need for a comprehensive overview and classification system, which we have devised based on structural characteristics. An updated overview is provided based on known tetronates, intended to spur further research in this field by identifying common structural features and general principles of their biosynthesis. We also compare a selection of chemical syntheses of representative compounds belonging to individual subtypes, both in terms of their efficiency as well as the extent to which they are biomimetic. This review also summarizes progress in unraveling some of the principles underlying the potent and varied bioactivities of natural tetronate antibiotics, and in identifying and better understanding their structure–activity relationships and modes of action.DFG, EXC 314, Unifying Concepts in Catalysi
The para-aminobenzoic acid-containing peptide albicidin is a pathogenicity factor synthesized by Xanthomonas albilineans in infections of sugar cane. Albicidin is a nanomolar inhibitor of the bacterial DNA gyrase with a strong activity against various Gram-negative bacteria. The bacterium Pantoea dispersa expresses the hydrolase AlbD, conferring natural resistance against albicidin. We show that AlbD is a novel type of endopeptidase that catalyzes the cleavage of albicidin at a peptide backbone amide bond, thus abolishing its antimicrobial activity. Additionally, we determined the minimal cleavage motif of AlbD with substrates derived by chemical synthesis. Our results clearly identify AlbD as a unique endopeptidase that is the first member of a new subfamily of peptidases. Our findings provide the molecular basis for a natural detoxification mechanism, potentially rendering a new tool in biological chemistry approaches.
Background No results of controlled trials are available for any of the few treatments offered to children with interstitial lung diseases (chILD). We evaluated hydroxychloroquine (HCQ) in a phase 2, prospective, multicentre, 1:1-randomized, double-blind, placebo-controlled, parallel-group/crossover trial. HCQ (START arm) or placebo were given for 4 weeks. Then all subjects received HCQ for another 4 weeks. In the STOP arm subjects already taking HCQ were randomized to 12 weeks of HCQ or placebo (= withdrawal of HCQ). Then all subjects stopped treatment and were observed for another 12 weeks. Results 26 subjects were included in the START arm, 9 in the STOP arm, of these four subjects participated in both arms. The primary endpoint, presence or absence of a response to treatment, assessed as oxygenation (calculated from a change in transcutaneous O2-saturation of ≥ 5%, respiratory rate ≥ 20% or level of respiratory support), did not differ between placebo and HCQ groups. Secondary endpoints including change of O2-saturation ≥ 3%, health related quality of life, pulmonary function and 6-min-walk-test distance, were not different between groups. Finally combining all placebo and all HCQ treatment periods did not identify significant treatment effects. Overall effect sizes were small. HCQ was well tolerated, adverse events were not different between placebo and HCQ. Conclusions Acknowledging important shortcomings of the study, including a small study population, the treatment duration, lack of outcomes like lung function testing below age of 6 years, the small effect size of HCQ treatment observed requires careful reassessments of prescriptions in everyday practice (EudraCT-Nr.: 2013-003714-40, www.clinicaltrialsregister.eu, registered 02.07.2013). Registration The study was registered on 2 July 2013 (Eudra-CT Number: 2013-003714-40), whereas the approval by BfArM was received 24.11.2014, followed by the approval by the lead EC of the University Hospital Munich on 20.01.2015. At clinicaltrials.gov the trial was additionally registered on November 8, 2015 (NCT02615938).
Mammalian spermatozoa are highly polarized cells composed of two morphological and functional units, each optimized for a special task. Although the apparent division into head and tail may as such represent the anatomical basis to avoid random diffusion of their special sets of signaling proteins and lipids, recent findings demonstrate the presence of lipid raft-derived membrane platforms and specific scaffolding proteins, thus indicating that smaller sub-domains exist in the two functional units of male germ cells. The aim of this review is to summarize new insights into the principles of subcellular organization in mammalian spermatozoa. Special emphasis is placed on recent observations indicating that an "acrosomal synapse" is formed by lipid raft-derived membrane micro-environments and multidomain scaffolding proteins. Both mechanisms appear to be responsible for ensuring the attachment of the huge acrosomal vesicle to the overlaying plasma membrane, as well as for preventing an accidental spontaneous loss of the single acrosome.
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