Structure Determination, Functional Characterization, and Biosynthetic Implications of Nybomycin Metabolites from a Mining Reclamation Site-Associated Streptomyces

  • J Nat Prod. 2019 Dec 27;82(12):3469-3476. doi: 10.1021/acs.jnatprod.9b01015.
Xiachang Wang  1 ,  Sherif I Elshahawi  2 ,  Larissa V Ponomareva ,  Qing Ye  3 ,  Yang Liu ,  Gregory C Copley  4 ,  James C Hower  4 ,  Bruce E Hatcher  5 ,  Madan K Kharel  6 ,  Steven G Van Lanen ,  Qing-Bai She  3 ,  S Randal Voss ,  Jon S Thorson ,  Khaled A Shaaban
Affiliations
  • 1. Jiangsu Key Laboratory for Functional Substances of Chinese Medicine , Nanjing University of Chinese Medicine , Nanjing 210023 , People's Republic of China.
  • 2. Department of Biomedical and Pharmaceutical Sciences , Chapman University School of Pharmacy , Irvine , California 92618 , United States.
  • 3. Markey Cancer Center, Department of Pharmacology and Nutritional Sciences, College of Medicine , University of Kentucky , Lexington , Kentucky 40536 , United States.
  • 4. Center for Applied Energy Research , University of Kentucky , Lexington , Kentucky 40511 , United States.
  • 5. Division of Water , Kentucky Energy and Environment Cabinet , 2642 Russellville Road , Bowling Green , Kentucky 42101 , United States.
  • 6. School of Pharmacy , University of Maryland Eastern Shore , Princess Anne , Maryland 21853 , United States.
PMID: 31833370 DOI: 10.1021/acs.jnatprod.9b01015
Abstract

We report the isolation and characterization of three new nybomycins (nybomycins B-D, 1-3) and six known compounds (nybomycin, 4; deoxynyboquinone, 5; α-rubromycin, 6; β-rubromycin, 7; γ-rubromycin, 8; and [2α(1E,3E),4β]-2-(1,3-pentadienyl)-4-piperidinol, 9) from the ROCK Creek (McCreary County, KY) underground coal mine acid reclamation site isolate Streptomyces sp. AD-3-6. Nybomycin D (3) and deoxynyboquinone (5) displayed moderate (3) to potent (5) Cancer cell line cytotoxicity and displayed weak to moderate anti-Gram-(+) Bacterial activity, whereas rubromycins 6-8 displayed little to no Cancer cell line cytotoxicity but moderate to potent anti-Gram-(+) Bacterial and Antifungal activity. Assessment of the impact of 3 or 5 Cancer cell line treatment on 4E-BP1 phosphorylation, a predictive marker of ROS-mediated control of cap-dependent translation, also revealed deoxynyboquinone (5)-mediated downstream inhibition of 4E-BP1p. Evaluation of 1-9 in a recently established axolotl embryo tail regeneration assay also highlighted the prototypical Telomerase Inhibitor γ-rubromycin (8) as a new inhibitor of tail regeneration. Cumulatively, this work highlights an alternative nybomycin production strain, a small set of new nybomycin metabolites, and previously unknown functions of rubromycins (Antifungal activity and inhibition of tail regeneration) and also provides a basis for revision of the previously proposed nybomycin biosynthetic pathway.