Antibacterial Thiopeptide GE2270-Congeners from Nonomuraea jiangxiensis

Abstract

Thiopeptides are macrocyclic natural products with potent bioactivity. Nine new natural thiopeptides (1−9) were obtained from a Nonomuraea jiangxiensis isolated from a terrestrial soil sample collected in Singapore. Even though some of these compounds were previously synthesized or isolated from engineered strains, herein we report the unprecedented isolation of these thiopeptides from a native Nonomuraea jiangxiensis. A comparison with the literature and a detailed analysis of the NMR and HRMS of compounds 1−9 was conducted to assign their chemical structures. The structures of all new compounds were highly related to the thiopeptide antibiotics GE2270, with variations in the substituents on the thiazole and amino acid moieties. Thiopeptides 1−9 exhibited a potent antimicrobial activity against the Gram-positive bacteria, Staphylococcus aureus with MIC90 values ranging from 2 µM to 11 µM. In addition, all compounds were investigated for their cytotoxicity against the human cancer cell line A549, none of the compounds were cytotoxic.

Keywords: GE2270; RiPPs; antibacterial; natural products; structure elucidation; thiopeptide.

Figure 1

Structures of thiostrepton, nosiheptide and GE2770A.

Figure 2

GNPS molecular networking of the crude extract of Nonomuraea jiangxiensis and the structures attributed to nodes in the thiopeptide GNPS clusters.

Figure 3

Chemical structures of compounds 1–9.

Figure 4

Selected COSY and HMBC correlations of 1 and 2.

Figure 5

Inhibitory effect dose response curve against Staphylococcus aureus Rosenbach (ATCC^® 25923™) for compounds 1–9 (A–I) and positive control gentamicin (J).

Figure 6

Phylogenetic tree showing the evolutionary relationship between A7611 and other type species of the genus Nonomuraea. Neighbor-joining phylogenetic tree was constructed based on 16S rRNA gene sequence showing the relationship between isolated strain A7611 and representatives or related actinobacteria strains retrieved from the GenBank with their respective accession numbers. Bootstrap values greater than 50% are shown at the number on the branches nodes which were analysed based on 1000 replicates. Bar, 0.01 substitutions per nucleotide position.