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Angew Chem Int Ed Engl. 2016 Mar 18;55(13):4220-5. doi: 10.1002/anie.201511348. Epub 2016 Mar 1.

Chemoreactive Natural Products that Afford Resistance Against Disparate Antibiotics and Toxins.

Author information

1
Department of Chemistry and Biochemistry, Natural Products Discovery Group, and Institute for Natural Products Applications and Research Technologies, University of Oklahoma, Norman, OK, 73019-5251, USA.
2
Department of Chemistry and Biochemistry, Natural Products Discovery Group, and Institute for Natural Products Applications and Research Technologies, University of Oklahoma, Norman, OK, 73019-5251, USA. rhcichewicz@ou.edu.

Abstract

Microorganisms use chemical inactivation strategies to circumvent toxicity caused by many types of antibiotics. Yet in all reported cases, this approach is limited to enzymatically facilitated mechanisms that each target narrow ranges of chemically related scaffolds. The fungus-derived shikimate analogues, pericoxide and pericosine A, were identified as chemoreactive natural products that attenuate the antagonistic effects of several synthetic and naturally derived antifungal agents. Experimental and computational studies suggest that pericoxide and pericosine A readily react via SN 2' mechanisms against a variety of nucleophilic substances under both in vitro aqueous and in situ co-culture conditions. Many of the substitution products from this reaction were highly stable and exhibited diminished toxicities against environmental fungal isolates, including the Tolypocladium sp. strain that produced pericoxide and pericosine A.

KEYWORDS:

antibiotic resistance; co-culture; fungi; isotope labeling; natural products; substitution reactions

PMID:
26928999
PMCID:
PMC4959538
DOI:
10.1002/anie.201511348
[Indexed for MEDLINE]
Free PMC Article

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