Chaxamycins A–D, Bioactive Ansamycins from a Hyper-arid Desert Streptomyces sp.

Abstract

Streptomyces sp. strain C34, isolated from soil collected in the Chilean hyper-arid Atacama Desert, was cultured on different media, resulting in the isolation and identification of four new ansamycin-type polyketides. The organism was selected for chemical investigation on the basis of a genome-mining PCR-based experiment targeting the gene encoding rifamycin-specific 3-amino-5-hydroxybenzoic acid synthetase (AHBA). The isolated compounds were structurally characterized using NMR and MS techniques and named chaxamycins A-D (1-4). Compounds 1-4 were tested for their antibacterial activity against Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 and for their ability to inhibit the intrinsic ATPase activity of the heat shock protein 90 (Hsp90). Chaxamycin D (4), which showed a selective antibacterial activity against S. aureus ATCC 25923, was tested further against a panel of MRSA clinical isolates. In a virtual screening experiment, chaxamycins A-D (1-4) have also been docked into the ATP-binding pocket in the N-terminal domain of the Hsp90, and the observed interactions are discussed.

Isolation and anti-HIV-1 integrase activity of lentzeosides A–F from extremotolerant lentzea sp. H45, a strain isolated from a high-altitude Atacama Desert soil

“…C38 and the cell invasion inhibitor chaxapeptin from S. leeuwenhoekii strain C58. [10][11][12][13][14][15][16] As part of our ongoing program to investigate the extremobiosphere as a source of new natural products, we have focused our attention on Lentzea sp. strain H45 which was isolated from a high-altitude Atacama Desert soil and shown to produce a specific pattern of secondary metabolites based on its liquid chromatography MS (LCMS) profile and associated NMR data.…”

Natural product diversity of actinobacteria in the Atacama Desert

“…6-9 also inhibited the intrinsic ATPase activity of human heat shock protein Hsp90 revealing promising antitumor activity with compound 6 about twofold less active than the positive standard, tanespimycin (17-N-allylamino-17-demethoxygeldanamycin). This latter result was corroborated by virtual docking studies which revealed that chaxamycins docked into the ATP binding pocket of Hsp90 where 6 exhibited the highest docking score (Rateb et al 2011a).…”

“…Owing to the difficulty of assigning the relative configuration of these types of compounds due to the conformational freedom of the ansa chain, the relative configuration of 6 was obtained by analysing its crystal structure using single-crystal X-ray diffraction. Using this information the relative configuration of the other three analogues was confirmed by comparing their ROESY spectra and coupling constants with that of 6 (Rateb et al 2011a). The lack of a methyl group at the olefinic C-16 next to the amide link is a characteristic structural feature of the new chaxamycins that distinguishes them from all previously known members of the naphthalenic ansamycin family.…”

“…Aminohydroxybenzoic acid (AHBA) synthetase is a wellknown target in genetic screening for novel compounds including ansamycin antibiotics. Consequently, genome mining of S. leeuwenhoekii C34 targeting the gene encoding rifamycin-specific AHBA synthase led to the discovery of four new ansamycin-type polyketides 6-9 (Rateb et al 2011a). Another class of compounds amenable to genome mining are ribosomally synthesized and post-translationally modified peptides (RiPPs).…”

“…Using genome-mining experiments that targeted the gene encoding 3-amino-5-hydroxybenzoic acid (AHBA) synthase, four ansamycin-type polyketides were isolated and characterised from S. leeuwenhoekii C34 T and named chaxamycins A-D (6-9) after the Laguna de Chaxa sampling site (Rateb et al 2011a). The planar structure of chaxamycins was confirmed by advanced NMR and HRMS techniques.…”