期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 142, 期 43, 页码 18369-18377出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.0c04675
关键词
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资金
- NIH/NIAD [1R01AI140400]
- Vanderbilt Institute of Chemical Biology
- D. Stanley and Ann T. Tarbell Endowment Fund
- American Heart Association Grant [12GRNT11920011]
- Deutsche Forschungsgemeinschaft (DFG) [WI3285/6-1]
- Howard Hughes Medical Institute
- NIH [CA68485, DK20593, DK58404, DK59637, EY08126, T32 HL007751]
- NIH/NIGMS [2P41 GM103391]
- DARPA [W911NF14-2-0022]
- Damon Runyon Cancer research foundation [DRG-2250-16]
- National Institutes of Health Shared Instrumentation Grant Program [1S10OD012359]
Many microorganisms possess the capacity for producing multiple antibiotic secondary metabolites. In a few notable cases, combinations of secondary metabolites produced by the same organism are used in important combination therapies for treatment of drug-resistant bacterial infections. However, examples of conjoined roles of bioactive metabolites produced by the same organism remain uncommon. During our genetic functional analysis of oxidase-encoding genes in the everninomicin producer Micromonospora carbonacea var. aurantiaca, we discovered previously uncharacterized antibiotics everninomicin N and O, comprised of an everninomicin fragment conjugated to the macrolide rosamicin via a rare nitrone moiety. These metabolites were determined to be hydrolysis products of everninomicin P, a nitrone-linked conjugate likely the result of nonenzymatic condensation of the rosamicin aldehyde and the octasaccharide everninomicin F, possessing a hydroxylamino sugar moiety. Rosamicin binds the erythromycin macrolide binding site approximately 60 angstrom from the orthosomycin binding site of everninomicins. However, while individual ribosomal binding sites for each functional half of everninomicin P are too distant for bidentate binding, ligand displacement studies demonstrated that everninomicin P competes with rosamicin for ribosomal binding. Chemical protection studies and structural analysis of everninomicin P revealed that everninomicin P occupies both the macrolide- and orthosomycin-binding sites on the 70S ribosome. Moreover, resistance mutations within each binding site were overcome by the inhibition of the opposite functional antibiotic moiety binding site. These data together demonstrate a strategy for coupling orthogonal antibiotic pharmacophores, a surprising tolerance for substantial covalent modification of each antibiotic, and a potential beneficial strategy to combat antibiotic resistance.
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