Chemoreactive Natural Products that Afford Resistance Against Disparate Antibiotics and Toxins |
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| Authors: | Dr Lin Du Dr Jianlan You Prof?Dr Kenneth M Nicholas Prof?Dr Robert H Cichewicz |
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| Institution: | Department of Chemistry and Biochemistry, Natural Products Discovery Group, and Institute for Natural Products Applications and Research Technologies, University of Oklahoma, Norman, OK, USA |
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| 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 SN2′ 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. |
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| Keywords: | antibiotic resistance co-culture fungi isotope labeling natural products substitution reactions |
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