Chemoreactive Natural Products that Afford Resistance Against Disparate Antibiotics and Toxins

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 fungal-derived shikimate analogues, pericoxide and pericosine A, were identified as chemoreactive natural products that attenuated the antagonistic effects of several synthetic and naturally derived antifungal agents. Experimental and computational studies suggested that pericoxide and pericosine A readily react via SN2′ mechanisms against a variety of nucleophilic substances under both in vitro aqueous and in situ coculture 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.

An Electrophilic Natural Product Provides a Safe and Robust Odor Neutralization Approach To Counteract Malodorous Organosulfur Metabolites Encountered in Skunk Spray

“…Considering the problems associated with existing “de-skunking” strategies, we set out to identify a safer and more effective skunk-spray-deodorizing solution. One of the lead substances to emerge from our search was the chemoreactive fungal metabolite pericosine A ( 4 ) (Figure ), which had been previously reported by our group to protect fungi from nucleophilic antibiotics/toxins . On the basis of those findings, we hypothesized that pericosine A and its synthetic analogues might offer an appealing solution to the neutralization of thiols and even thioacetates via S N 2′ substitution mechanisms under aqueous conditions.…”

Synthesis of Natural O-Linked Carba-Disaccharides, (+)- and (−)-Pericosine E, and Their Analogues as α-Glucosidase Inhibitors

“…As mentioned above, donor 9 could be derived from syn -epoxide 11 , which corresponds with a pericoxide proven to be the precursor of pericosine A in the culture of Tolypocladium sp. [ 27 ]. Therefore, our strategy might be biomimetic.…”

“…Recently, the Cichewicz group reported the isolation of maximiscin, which shows potent inhibition against melanoma cell line UACC-62 and contains a pericosine moiety, as a fungal metabolite of Tolypocladium sp. [ 26 , 27 ]. However, our attention was focused on the co-isolation of (+)-pericosine A ( 1 ) and precursor pericoside ( 7 ) from the fungal extract (our second synthetic intermediate, syn -epoxide 11 , extracted later) [ 27 ].…”

“…[ 26 , 27 ]. However, our attention was focused on the co-isolation of (+)-pericosine A ( 1 ) and precursor pericoside ( 7 ) from the fungal extract (our second synthetic intermediate, syn -epoxide 11 , extracted later) [ 27 ]. These natural products can reduce the antifungal activities of antibiotics.…”

Precursor-Directed Biosynthesis of Aminofulvenes: New Chalanilines from Endophytic Fungus Chalara sp.

“…One example is the compound maximiscin from Tolypocladium sp. which results from highly reactive intermediates that can detoxify various synthetic and naturally derived antifungals via nucleophilic substitutions [ 11 ]. Previously, we found that the endophyte Chalara sp.…”