Planta Med 2012; 78 - PI66
DOI: 10.1055/s-0032-1320753

Isolation of novel anti-TB cyclohexapeptides from actinomycetes

G Cai 1, 2, JG Napolitano 2, J McAlpine 2, S Cho 1, Y Wang 1, BU Jaki 1, 2, JW Suh 3, SH Yang 3, IA Lee 3, GF Pauli 1, 2, SG Franzblau 1, 2
  • 1Institute for Tuberculosis Research
  • 2Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S Wood St, Chicago, IL 60612, USA
  • 3Center for Nutraceutical and Pharmaceutical Materials, Myongji University, Cheoin-gu, Yongin, Gyeonggi-Do 449–728, Korea

Thirty-five thousand actinomycete extracts were screened for anti-TB activity, followed by C18 cartridge fractionation of 37 prioritized extracts. Based on MICs against replicating and non-replicating M. tuberculosis (Mtb), and IC50s against Vero cells to generate selectivity indices, seven fractions were selected for further separation. ECUM14046, a Streptomyces hygroscopicus strain, when cultured in GSS media and extracted with ethyl acetate, yielded a fraction with potent anti-TB activity. This fraction had a well-defined thin layer chromatography (TLC) profile and was therefore further fractionated using preparative HPLC. The molecular formulas of two purified components, designated as hytramycin-V and hytramycin-I, were determined by high-resolution mass spectrometry (ESI-IT-TOF) as C30H51N9O6 and C31H53N9O6, resp. Structure elucidation by 1D/2D NMR revealed both to be cyclohexapeptides with three unusual piperazic acid moieties. The MICs against replicating and especially non-replicating Mtb fall into the range of existing anti-TB drugs, such as streptomycin and capreomycin, and were maintained against Mtb strains that represent the major global clades, as well as H37Rv-isogenic strains that are resistant to individual clinical anti-TB drugs.