Novel insights into the antibacterial activities of cannabinoid biosynthetic intermediate, olivetolic acid, and its alkyl-chain derivatives

Abstract

Investigations of antibacterial activities revealed that the incorporation of longer alkyl chains to the C-6 position in resorcylic acid conferred antibacterial properties against Staphylococcus aureus and Bacillus subtilis . The resultant olivetolic acid (OA) derivatives with n -undecyl and n -tridecyl side-chains, even those lacking the hydrophobic geranyl moiety from their C-3 positions, exhibited strong antibacterial activities against B. subtilis at a MIC value of 2.5 μM. Furthermore, the study demonstrated that the n -heptyl alkyl-chain modification at C-6 of cannabigerolic acid (CBGA) effectively enhanced the activity against B. subtilis , demonstrating the importance of the alkyl side-chain in modulating the bioactivity. Overall, the findings in this study provided insight into further evaluations of the antibacterial activities, as well as other various biological activities of OA and CBGA derivatives, especially with optimized hydrophobicities at both the alkyl and prenyl side-chain positions of the core skeleton for the discovery of novel drug seeds. Supplementary Information The online version contains supplementary material available at 10.1007/s11418-022-01672-9.

Generation of Cannabigerolic Acid Derivatives and Their Precursors by Using the Promiscuity of the Aromatic Prenyltransferase NphB

“…Due to its size, an extended or branched alkyl chain attached to the resorcylate core will is likely to fit into the pocket. This has been demonstrated in converting an analog containing a tridecane side chain to CBGA‐C13, but the ratio of possible products formed is unknown [25] . Previous studies have reported that olivetolic acid derivatives with shorter alkyl chains, such as the methyl or propyl chain, are converted to CBGA‐C1 and CBGA‐C3, respectively.…”

“…This has been demonstrated in converting an analog containing a tridecane side chain to CBGA-C13, but the ratio of possible products formed is unknown. [25] Previous studies have reported that olivetolic acid derivatives with shorter alkyl chains, such as the methyl or propyl chain, are converted to CBGA-C1 and CBGA-C3, respectively. Orsellinic acid is converted to various products by the NphB wild type.…”

Engineering cannabinoid production in Saccharomyces cerevisiae

“…Furthermore, recent in vitro studies highlight the potential of NphB to produce of both natural and unnatural derivatives of CBGA‐C5. [ 30,31 ]…”

“…Furthermore, recent in vitro studies highlight the potential of NphB to produce of both natural and unnatural derivatives of CBGA-C5. [30,31] A first in vivo approach of NphB using E. coli as heterologous host organism for the production of CBGA-C5 and CBGA-C3 was reported in 2019. The group produced 1 mg L −1 CBGA-C5 from glycerol and 200 mg L −1 OA, as well as 5 mg L −1 CBGA-C3 from glycerol and 200 mg L −1 divarinic acid.…”

Computational assessment of the primary and secondary antioxidant potential of alkylresorcinols in physiological media

“…22 It has been found to have antifungal and antibacterial properties, as well as potential anti-inammatory and anti-cancer effects. 23,24 However, despite their promising biological properties, limited studies have been conducted on their antioxidant capacity. This is a signicant limitation, as these compounds have the potential to be used as natural alternatives to toxic synthetic compounds like BHT and BHA, which are commonly used as preservatives in the food industry.…”