Quantification of the content of cannabinol in commercially available e-liquids and studies on their thermal and photo-stability.

Cannabidiol (CBD) has become a buzzword in many products that have bloomed on the market. The scientific community and some authorities have recently raised concerns on the quality of these products. In particular, the discrepancy between the labelled and the real content of cannabidiol in liquids for e-cigarettes seems to be emerging as a major issue. Furthermore, to-date no studies have been carried out on the chemical stability upon storage of these type of products. The aim of this work was to investigate the accuracy in labelling of thirteen commercially e-liquids containing CBD and the effects of different storage conditions on their quality. The results showed that only 38% of samples were labelled within a ±10% variance from their labels. Stability tests showed a maximum degradation of CBD when samples were stored at 37 °C for 30 days with average values up to 20%. The effect of light was lower but still significant with averages values up to 15% degradation after 30 days. In conclusion, we believe that health authorities should regulate and control this market more stringently to protect customers and their health. Furthermore, our stability tests have shown that if clear indications are provided on the best storage conditions, the quality of these products can be mostly preserved.

Antibacterial Nucleoside-Analog Inhibitor of Bacterial RNA Polymerase.

Drug-resistant bacterial pathogens pose an urgent public-health crisis. Here, we report the discovery, from microbial-extract screening, of a nucleoside-analog inhibitor that inhibits bacterial RNA polymerase (RNAP) and exhibits antibacterial activity against drug-resistant bacterial pathogens: pseudouridimycin (PUM). PUM is a natural product comprising a formamidinylated, N-hydroxylated Gly-Gln dipeptide conjugated to 6'-amino-pseudouridine. PUM potently and selectively inhibits bacterial RNAP in vitro, inhibits bacterial growth in culture, and clears infection in a mouse model of Streptococcus pyogenes peritonitis. PUM inhibits RNAP through a binding site on RNAP (the NTP addition site) and mechanism (competition with UTP for occupancy of the NTP addition site) that differ from those of the RNAP inhibitor and current antibacterial drug rifampin (Rif). PUM exhibits additive antibacterial activity when co-administered with Rif, exhibits no cross-resistance with Rif, and exhibits a spontaneous resistance rate an order-of-magnitude lower than that of Rif. PUM is a highly promising lead for antibacterial therapy.

Family of class I lantibiotics from actinomycetes and improvement of their antibacterial activities.

Lantibiotics, an abbreviation for "lanthionine-containing antibiotics", interfere with bacterial metabolism by a mechanism not exploited by the antibiotics currently in clinical use. Thus, they have aroused interest as a source for new therapeutic agents because they can overcome existing resistance mechanisms. Starting from fermentation broth extracts preselected from a high-throughput screening program for discovering cell-wall inhibitors, we isolated a series of related class I lantibiotics produced by different genera of actinomycetes. Analytical techniques together with explorative chemistry have been used to establish their structures: the newly described compounds share a common 24 aa sequence with the previously reported lantibiotic planosporicin (aka 97518), differing at positions 4, 6, and 14. All of these compounds maintain an overall -1 charge at physiological pH. While all of these lantibiotics display modest antibacterial activity, their potency can be substantially modulated by progressively eliminating the negative charges, with the most active compounds carrying basic amide derivatives of the two carboxylates originally present in the natural compounds. Interestingly, both natural and chemically modified lantibiotics target the key biosynthetic intermediate lipid II, but the former compounds do not bind as effectively as the latter in vivo. Remarkably, the basic derivatives display an antibacterial potency and a killing effect similar to those of NAI-107, a distantly related actinomycete-produced class I lantibiotic which lacks altogether carboxyl groups and which is a promising clinical candidate for treating Gram-positive infections caused by multi-drug-resistant pathogens.

Halogenated spirotetronates from Actinoallomurus.

Two new members of the spirotetronate class, nai414-A and nai414-B, were discovered and isolated from an Actinoallomurus sp. Their structures were established by 1D and 2D NMR, UV, and MS analyses and by chemical degradation. They showed antimicrobial and antitumor activity against Gram-positive bacteria and against human microvascular endothelial cells, respectively. Substituting bromide for chloride ions in the growth medium afforded mono- and dibrominated derivatives.

γ-Lactones from δ-lactones: total synthesis of the biosynthetic derailment product mupirocin H.

Two different strategies for the synthesis of functionalised γ-lactones from δ-lactones are described and used in a convergent synthesis of (+)-mupirocin H. The total synthesis is versatile and may be readily adapted for the preparation of further truncated metabolites from Pseudomonas fluorescens.

The genus Actinoallomurus and some of its metabolites.

In the search for novel antibiotics, natural products continue to represent a valid source of bioactive molecules. During a program aimed at identifying previously unreported taxa of actinomycetes as potential source of novel compounds, we isolated hundreds of different representatives of a new group, initially designated as 'Alpha' and independently described as Actinoallomurus. We report on a PCR-specific method for the detection of this taxon, on appropriate growth conditions and on a pilot-screening program on 78 strains. The strains produce antibacterial or antifungal compounds at a relatively high frequency. Four strains were characterized in further detail: one produced the aromatic polyketide benanomicin B and its dexylosyl derivative; a second strain produced N-butylbenzenesulfonamide; a third strain was an efficient converter of soymeal isoflavonoids from soymeal constituents; and a fourth strain produced several coumermycin-related aminocoumarins, with coumermycin A2 as the major peak, and with some new congeners as minor components of the complex. These data suggest that Actinoallomurus strains possess several pathways for secondary metabolism and represent an attractive source in the search for novel antibiotics.

In vivo mutational analysis of the mupirocin gene cluster reveals labile points in the biosynthetic pathway: the "leaky hosepipe" mechanism.

A common feature of the mupirocin and other gene clusters of the AT-less polyketide synthase (PKS) family of metabolites is the introduction of carbon branches by a gene cassette that contains a beta-hydroxy-beta-methylglutaryl CoA synthase (HMC) homologue and acyl carrier protein (ACP), ketosynthase (KS) and two crotonase superfamily homologues. In vivo studies of Pseudomonas fluorescens strains in which any of these components have been mutated reveal a common phenotype in which the two major isolable metabolites are the truncated hexaketide mupirocin H and the tetraketide mupiric acid. The structure of the latter has been confirmed by stereoselective synthesis. Mupiric acid is also the major metabolite arising from inactivation of the ketoreductase (KR) domain of module 4 of the modular PKS. A number of other mutations in the tailoring region of the mupirocin gene cluster also result in production of both mupirocin H and mupiric acid. To explain this common phenotype we propose a mechanistic rationale in which both mupirocin H and mupiric acid represent the products of selective and spontaneous release from labile points in the pathway that occur at significant levels when mutations block the pathway either close to or distant from the labile points.