Journal
ACS CHEMICAL BIOLOGY
Volume 12, Issue 12, Pages 3093-3102Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.7b00688
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Funding
- University of Wisconsin-Madison School of Pharmacy
- University of Wisconsin Institute for Clinical and Translational Research through NIH/NCATS [UL1TR000427]
- NIH through the administration of NIGMS [R01GM104192, R01GM104975]
- NIDDK [R01DK071801]
- HGRI [R01HG005084, 1R01HG0050]
- NIH [T32GM008347, T32GM008505, NIH-NCRR S10RR029531, P41GM103399, RR02781, RR08438]
- NSF [00039202, DMB-8415048, OIA-9977486, BIR-9214394]
- Office of the Vice Chancellor for Research and Graduate Education at the University of Wisconsin-Madison
- University of Wisconsin
- USDA
- Vilas Distinguished Achievement Professorship
- Janis Apinis Professorship
- Wisconsin Alumni Research Foundation
- [U19-AI109673]
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Advances in genomics and metabolomics have made clear in recent years that microbial biosynthetic capacities on Earth fa exceed previous expectations. This is attributable, in part, to the realization that most Microbial natural product (NP) producers harbor biosynthetic machineries not readily amenable to classical laboratory fermentation conditions. Such cryptic or dormant biosynthetic gene clusters (BGCs) encode for a vast assortment of potentially new antibiotics and, as such, have become extremely attractive targets for activation under controlled laboratory conditions. We report here that coculturing of a Rhodococcus sp. and a Micromonospora sp. affords keyicin, a new and otherwise unattainable bis-nitroglycosylated anthracycline whose mechanism of action (MOA) appears to deviate from those of other anthracyclines. The structure of keyicin was elucidated using high resolution MS and NMR technologies, as well as detailed molecular modeling studies. Sequencing of the keyicin BGC (within the Micromonospora genome) enabled-both structural and genomic comparisons to other anthracycline-producing, systems informing efforts to characterize keyicin. The new NP was found to be selectively active against Gram-positive bacteria including both Rhodococcus Sp. and Mycobacterium sp. E. coli-based chemical genomics studies revealed that keyicin's MOA, in contrast to Many other anthracyclines, does not invoke nucleic acid damage.
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