Search

DNA topoisomerases are attractive targets for anticancer agents. Dual topoisomerase I/II inhibitors are particularly appealing due to their reduced rates of resistance. A number of therapeutically relevant topoisomerase inhibitors are bacterial natural products. Mining the untapped chemical diversity encoded by soil microbiomes presents an opportunity to identify additional natural topoisomerase inhibitors. Here we couple metagenome mining, bioinformatic structure prediction algorithms, and chemical synthesis to produce the dual topoisomerase inhibitor tapcin. Tapcin is a mixed p‐aminobenzoic acid (PABA)‐thiazole with a rare tri‐thiazole substructure and picomolar antiproliferative activity. Tapcin reduced colorectal adenocarcinoma HT‐29 cell proliferation and tumor volume in mouse hollow fiber and xenograft models, respectively. In both studies it showed similar activity to the clinically used topoisomerase I inhibitor irinotecan. The study suggests that the interrogation of soil microbiomes using synthetic bioinformatic natural product methods has the potential to be a rewarding strategy for identifying potent, biomedically relevant, antiproliferative agents. [ABSTRACT FROM AUTHOR]

Natural products are a major source of new antibiotics. Here we utilize biosynthetic instructions contained within metagenome‐derived congener biosynthetic gene clusters (BGCs) to guide the synthesis of improved antibiotic analogues. Albicidin and cystobactamid are the first members of a new class of broad‐spectrum ρ‐aminobenzoic acid (PABA)‐based antibiotics. Our search for PABA‐specific adenylation domain sequences in soil metagenomes revealed that BGCs in this family are common in nature. Twelve BGCs that were bio‐informatically predicted to encode six new congeners were recovered from soil metagenomic libraries. Synthesis of these six predicted structures led to the identification of potent antibiotics with changes in their spectrum of activity and the ability to circumvent resistance conferred by endopeptidase cleavage enzymes. [ABSTRACT FROM AUTHOR]

The development of novel antibiotics is critical to combating the growing emergence of drug‐resistant pathogens. Malacidin A is a new member of the calcium‐dependent antibiotic (CDAs) family with activity against antibiotic‐resistant pathogens. Its mode of action is distinct from classical CDAs. However, the absolute structure of malacidin A has not been established. Herein, the total syntheses of malacidin A and its analogues are reported by a combination of Fmoc‐based solid‐phase peptide synthesis (SPPS) and β‐hydroxyaspartic acid ligation‐mediated peptide cyclization. The total synthesis enabled us to establish the absolute configuration of malacidin A, which is in agreement with those for natural malacidin A confirmed by advanced Marfey's analysis in our study. [ABSTRACT FROM AUTHOR]

Sequenzmarkergesteuertes Screening von DNA ‐ Bibiotheken in Bodenmikroben kann das Auffinden neuer Verbindungen mit verbesserten Eigenschaften ermöglichen. In heterologen Expressionsexperimenten kodiert der von eDNA abgeleitete arm ‐ Cluster für das Anthracyclin Arimetamycin A (siehe Bild), das wirksamer ist als klinisch eingesetzte natürliche Anthracycline und seine Aktivität gegen multiwirkstoffresistente (MDR) Krebszellen behält. [ABSTRACT FROM AUTHOR]

The article discusses research on glycopeptide sulfotransferase Teg14 and the 2.7 Å resolution structure. The study involved cloning Teg14 from a DNA environmental library, transformation of Teg14 to its protein expression and crystallization and x-ray diffraction of Teg 14 through the Joint Center for Structural Genomics (JCSG) suites including Cores I-IV from Qiagen. Results indicated that GHL helix is adopting the bent formation in Teg 14 in all structures of glycopeptide sulfotransferase as observed in Teg 12 structure.

Pass auf, da ist überall neue Chemie In der Zuschrift auf S. 11269 ff. beschreiben S. F. Brady und H. ‐ S. Kang ein hochwirksames neues Anthracyclin, das durch “Mining” von Bodenmikroben ‐ DNA entdeckt wurde. Aus dem Boden der Sonora ‐ Wüste (USA) extrahierte DNA wurde nach Genclustern durchsucht, von denen die Herstellung neuer Naturstoffe zu erwarten war. Der aus dieser DNA abgeleitete arm ‐ Cluster kodiert für Arimetamycin A, ein Anthracyclin, das gegen multiwirkstoffresistente Krebszellen aktiv und wirksamer als die derzeit in der Krebstherapie eingesetzten natürlichen Anthracycline ist. [ABSTRACT FROM AUTHOR]

Watch your step, there is new chemistry everywhere In their Communication on page 11063 ff., S. F. Brady and H.‐S. Kang describe a potent new anthracycline discovered by soil‐DNA mining methods. DNA extracted from Sonoran Desert soil (USA) was screened for gene clusters predicted to produce new natural products. The soil‐DNA‐derived arm cluster encodes arimetamycin A, an anthracycline that is active against multidrug‐resistant cancer cells and more potent than natural anthracyclines currently used in cancer therapy. [ABSTRACT FROM AUTHOR]