Isolation, characterization, and bioactivity profiling of oxazoline containing madurastatin siderophores from Actinomadura sp.

Nine new hydroxyphenyloxazolines, madurastatin B4, C2, D3 and D4, E1 and E2, F1 as well as G1 and G2 (8-16), along with two new enantiomers of madurastatin D1 (ent-6) and D2 (ent-7) and two known congeners, madurastatin B1 (2) and C1 (5), were isolated from the liquid culture of Actinomadura sp. ST100801 based on the initial activity against Escherichia coli screened in bicarbonate-supplemented Mueller Hinton II medium and identification via molecular networking. Structure elucidation was achieved by comprehensive 1D and 2D NMR as well as MS/MS fragmentation analyses. Their absolute configuration was determined by Marfey's analysis. Complemented with functionalized hydroxyphenyloxazolines (2, 4, 17-18) obtained by total synthesis, the isolated compounds were evaluated for antibacterial activities revealing MICs down to 4 µg ml-1 against Moraxella catarrhalis. Therefore, this study enlarges the family of madurastatin siderophores.

Genomic and Chemical Decryption of the Bacteroidetes Phylum for Its Potential to Biosynthesize Natural Products.

With progress in genome sequencing and data sharing, 1,000s of bacterial genomes are publicly available. Genome mining-using bioinformatics tools in terms of biosynthetic gene cluster (BGC) identification, analysis, and rating-has become a key technology to explore the capabilities for natural product (NP) biosynthesis. Comprehensively, analyzing the genetic potential of the phylum Bacteroidetes revealed Chitinophaga as the most talented genus in terms of BGC abundance and diversity. Guided by the computational predictions, we conducted a metabolomics and bioactivity driven NP discovery program on 25 Chitinophaga strains. High numbers of strain-specific metabolite buckets confirmed the upfront predicted biosynthetic potential and revealed a tremendous uncharted chemical space. Mining this data set, we isolated the new iron chelating nonribosomally synthesized cyclic tetradeca- and pentadecalipodepsipeptide antibiotics chitinopeptins with activity against Candida, produced by C. eiseniae DSM 22224 and C. flava KCTC 62435, respectively. IMPORTANCE The development of pipelines for anti-infectives to be applied in plant, animal, and human health management are dried up. However, the resistance development against compounds in use calls for new lead structures. To fill this gap and to enhance the probability of success for the discovery of new bioactive natural products, microbial taxa currently underinvestigated must be mined. This study investigates the potential within the bacterial phylum Bacteroidetes. A combination of omics-technologies revealed taxonomical hot spots for specialized metabolites. Genome- and metabolome-based analyses showed that the phylum covers a new chemical space compared with classic natural product producers. Members of the Bacteroidetes may thus present a promising bioresource for future screening and isolation campaigns.

The Discovery and Structure-Activity Evaluation of (+)-Floyocidin B and Synthetic Analogs.

Tuberculosis represents one of the ten most common courses of death worldwide and the emergence of multidrug-resistant M. tuberculosis makes the discovery of novel anti-tuberculosis active structures an urgent priority. Here, we show that (+)-floyocidin B representing the first example of a novel dihydroisoquinoline class of fungus-derived natural products, displays promising antitubercular hit properties. (+)-Floyocidin B was identified by activity-guided extract screening and its structure was unambiguously determined by total synthesis. The absolute configuration was deduced from a key synthesis intermediate by single crystal X-ray diffraction analysis. A hit series was generated by the isolation of further natural congeners and the synthesis of analogs of (+)-floyocidin B. Extensive biological and physicochemical profiling of this series revealed first structure-activity relationships and set the basis for further optimization and development of this novel antitubercular scaffold.

Total Synthesis and Structure Revision of (-)-Avicennone C.

All four possible stereoisomers of the natural product (-)-avicennone C were synthesized using two different methods for ring closure. The absolute stereochemistry was elucidated unambiguously by comparison of the analytical data with those of the reported natural product and by single X-ray crystal diffraction of synthetic intermediates. The proposed structure needed to be revised with regard to the absolute configuration of the stereogenic center bearing the secondary hydroxyl group. The reported synthesis offers a flexible, selective, and efficient access to all possible stereoisomers and may be of value for the stereoselective synthesis of other epoxyquinone natural products.