ObjectivesTo investigate beliefs about medicines and their association with medicine adherence in patients with chronic diseases in China.DesignA cross-sectional questionnaire-based studySettingTwo large urban hospitals in Hefei and Tianjin, ChinaParticipantsHospital inpatients (313 stroke patients) and outpatients (315 diabetic patients and 339 rheumatoid arthritis (RA) patients) were recruited between January 2014 and September 2014.Outcome measuresThe Beliefs about Medicines Questionnaire (BMQ), assessing patients’ beliefs about the specific medicine (Specific-Necessity and Specific-Concerns) prescribed for their conditions (stroke/diabetes/RA) and more general background beliefs about pharmaceuticals as a class of treatment (BMQ-General Benefit, Harm and Overuse); the Perceived Sensitivity to Medicines scale (PSM) assessed patients’ beliefs about how sensitive they were to the effects of medicines and the Medication Adherence Report Scale. The association between non-adherence and beliefs about medicines was assessed using a logistic regression model.ResultsPatients with diabetes mellitus had a stronger perceived need for treatment (mean (SD) Specific-Necessity score, 3.75 (0.40)) than patients with stroke (3.69 (0.53)) and RA (3.66 (0.44)) (p=0.049). Moderate correlations were observed between Specific-Concerns and General-Overuse, General-Harm and PSM (Pearson correlation coefficients, 0.39, 0.49 and 0.49, respectively, p<0.01). Three hundred and eleven patients were non-adherent to their medicine (159 (51.0%) in the stroke group, 60 (26.7%) in the diabetes mellitus group and 62 (19.8%) in the RA group, p<0.01). Across the whole sample, after adjusting for demographic characteristics, non-adherence was associated with patients who had higher concerns about their medicines (OR, 1.35, 95% CI 1.07 to 1.71) and patients who believed that they were personally sensitive to the effects of medications (OR 1.44, 95% CI 1.16 to 1.85).ConclusionThe BMQ is a useful tool to identify patients at risk of non-adherence. In the future, adherence intervention studies may use the BMQ to screen for patients who are at risk of non-adherence and to map interventional support.

The RNA polymerase inhibitor tiacumicin B is currently undergoing phase III clinical trial for treatment of Clostridium difficile associated diarrhea with great promise. To understand the biosynthetic logic and to lay a foundation for generating structural analogues via pathway engineering, the tiacumicin B biosynthetic gene cluster was identified and characterized from the producer Dactylosporangium aurantiacum subsp. hamdenensis NRRL 18085. Sequence analysis of a 110,633 bp DNA region revealed the presence of 50 open reading frames (orfs). Functional investigations of 11 orfs by in vivo inactivation experiments, preliminarily outlined the boundaries of the tia-gene cluster and suggested that 31 orfs were putatively involved in tiacumicin B biosynthesis. Functions of a halogenase (TiaM), two glycosyltransferases (TiaG1 and TiaG2), a sugar C-methyltransferase (TiaS2), an acyltransferase (TiaS6), and two cytochrome P450s (TiaP1 and TiaP2) were elucidated by isolation and structural characterization of the metabolites from the corresponding gene-inactivation mutants. Accumulation of 18 tiacumicin B analogues from 7 mutants not only provided experimental evidence to confirm the proposed functions of individual biosynthetic enzymes, but also set an example of accessing microbial natural product diversity via genetic approach. More importantly, biochemical characterization of the FAD-dependent halogenase TiaM reveals a sequentially acting dihalogenation step tailoring tiacumicin B biosynthesis.

Xiamycin A (XMA) and oxiamycin (OXM) are bacterial indolosesquiterpenes featuring rare pentacyclic ring systems and are isolated from a marine-derived Streptomyces sp. SCSIO 02999. The putative biosynthetic gene cluster for XMA/OXM was identified by a partial genome sequencing approach. Eighteen genes were proposed to be involved in XMA/OXM biosynthesis, including five genes for terpene synthesis via a non-mevalonate pathway, eight genes encoding oxidoreductases, and five genes for regulation and resistance. Targeted disruptions of 13 genes within the xia gene cluster were carried out to probe their encoded functions in XMA/OXM biosynthesis. The disruption of xiaK, encoding an aromatic ring hydroxylase, led to a mutant producing indosespene and a minor amount of XMA. Feeding of indosespene to XMA/OXM nonproducing mutants revealed indosespene as a common precursor for XMA/OXM biosynthesis. Most notably, the flavin dependent oxygenase XiaI was biochemically characterized in vitro to convert indosespene to XMA, revealing an unusual oxidative cyclization strategy tailoring indolosesquiterpene biosynthesis.

Four new indolo‐sesquiterpenes – dixiamycins A (1) and B (2), oxiamycin (3), and chloroxiamycin (4) – were isolated from a marine‐derived Actinomycete and characterized, together with the known compound xiamycin A (5). Dixiamycins A (1) and B (2) are the first examples of atropisomerism of naturally occurring N‐N‐coupled atropo‐diastereomers, with a dimeric indolo‐sesquiterpene skeleton and a stereogenic N‐N axis between sp3‐hybridized nitrogen atoms. Solution TDDFT ECD calculations were utilized to ascertain the axial chirality of 1 and 2, and rotational barriers and transitions states of the inversion were calculated. Oxiamycin (3) contains a seven‐membered 2,3,4,5‐tetrahydrooxepine ring. The two dimeric compounds 1 and 2 showed better antibacterial activities than the monomers 3–5.

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Ikarugamycin is a member of the polycyclic tetramate macrolactams (PTMs) family of natural products with diverse biological activities. The biochemical mechanisms for the formation of polycyclic ring systems in PTMs remain elusive. The enzymatic mechanism of constructing an inner five-membered ring in ikarugamycin is reported. A three-genecassette ikaABC from the marine-derived Streptomyces sp. ZJ306 is sufficient for conferring ikarugamycin production in a heterologous host. IkaC catalyzes a reductive cyclization reaction to form the inner five-membered ring by a Michael addition-like reaction. This study provides the first biochemical evidence for polycycle formation in PTMs and suggests a reductive cyclization strategy which may be potentially applicable in general to the corresponding ring formation in other PTMs.

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