Hytramycins V and I, Anti-Mycobacterium tuberculosis Hexapeptides from a Streptomyces hygroscopicus Strain

Abstract

Thirty-five thousand actinomycete extracts were screened for anti-Mycobacterium tuberculosis (M. tb) activity, followed by C18 cartridge fractionation of 37 prioritized extracts. Based on MICs against replicating and nonreplicating M. tb, and IC50 values against Vero cells to generate selectivity indices, seven fractions from seven different strains were selected for further examination. When cultured in G.S.S. media and extracted with ethyl acetate, the Streptomyces hygroscopicus strain ECUM 14046 yielded an extract with promising anti-M. tb activity and a well-defined chromatographic profile. Fractionation by preparative HPLC and subsequent structure elucidation of two active fractions using 1D- and 2D-NMR and MS methods revealed the presence of two cyclohexapeptides, hytramycins V and I, each containing three unusual piperazic acid moieties. The use of (1)H iterative full spin analysis (HiFSA) on both hytramycins confirmed that quantum mechanics-simulated spectra match the experimental data, and all J(H,H) and δH values are consistent with the proposed structures. The absolute configuration of each amino acid moiety was determined by Marfey's method. The MICs against replicating and, more importantly, nonreplicating M. tb fall into the range of some existing second-line anti-TB drugs, such as streptomycin and capreomycin, respectively. The activities were maintained against M. tb strains that represent the major global clades, as well as H37Rv-isogenic strains that are resistant to individual clinical anti-TB drugs.

A New Cyclic Hexapeptide and a New Isocoumarin Derivative from the Marine Sponge-Associated Fungus Aspergillus similanensis KUFA 0013

“…CNX037, isolated from sediment. Cai et al [ 37 ] have isolated two anti- Mycobacterium tuberculosis cyclohexapeptides from a Streptomyces hygroscopicus Strain, while Song et al [ 38 ] reported isolation of three new cyclopeptides, desotamides B–D, from the deep South China Sea-derived Streptomyces scopuliridis SCSIO ZJ46. To the best of our knowledge, compound 2 is the first cyclopeptide containing d -pipecolic acid residue ever isolated from marine fungi.…”

Design, synthesis and structure-activity relationship study of wollamide B; a new potential anti TB agent

“…Several small and ultra-small cyclic peptides were reported to exert antimycobacterial activities, including griselmycins [28], depsidomycin [29], hytramycin [30], brunsvicamides [31], pyridomycin [32], hirsutellide A [33] and the wollamides [34]. …”

Bioautography with TLC-MS/NMR for Rapid Discovery of Anti-tuberculosis Lead Compounds from Natural Sources

“…13 The ethyl acetate extract of ECUM14046 and the daughter fraction F3 were spotted on the NP-TLC plate, developed with EtOAc/Tol/MeOH/FA (95%) (60:40:5:1, v/v/v/v), and subjected to contact bioautography (Figure 4B). The zones of interest corresponding to the zones of inhibition on the agar plate were localized on the duplicate TLC plate ( R f 0.44 and 0.53).…”