title: 1α,2α-Epoxy-3β-hydroxy oleanolic acid derivatives regulation of the metabolism, haemolysis and β-lactamase gene expression in vitro and their structure-microbicidal activity relationship.
abstract: Oleanolic acid (OA), one of the major pentacyclic triterpenes abundantly present in nature, is a promising compound with various biological activities, including anti-inflammatory, anti-ulcer, hepatoprotective, antidiabetic, fungicidal and antiparasitic properties. Therefore, a series of derivatives of 1α,2α-epoxy-3β-hydroxyl oleanolic acid derivatives were designed and synthesized, and their antibacterial activities were investigated in vitro. Based on these results, the compounds with antibacterial activity were screened by RT-PCR to determine whether they can regulate the expression of genes related to metabolism, haemolysis, and β-lactamase in vitro, and the structure-microbicidal activity relationship of each compound was analyzed. Our study shows that some of the modifications in the synthetic compounds, such as the introduction of an ortho-cyano-substituted benzyl group and a short chain alkyl ester at the 28-carboxyl, as well as the introduction of an acetyl group at the 3-hydroxyl group of ring A, could enhance antibacterial activity. This provides basic evidence for the optimization of 1α,2α-epoxy-3β-hydroxyl oleanolic acid derivatives. The antibacterial mechanism of the active OA derivatives appears to involve the regulation of expression of metabolism-associated genes in Escherichia coli, haemolysis-associated genes in Bacillus subtilis, metabolism-related genes in Klebsiella pneumonia and β-lactamase-associated genes in Acinetobacter baumannii. Some OA derivatives were bactericidal to three of the strains and appeared to regulate gene expression associated with metabolism, haemolysis, and β-lactamase in vitro. These newly designed OA derivatives possess unique antibacterial activities and may be potentially useful for prophylactic or therapeutic intervention of bacterial infections.
authors.affiliation: Guizhou University, Guiyang, Guizhou, China; Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 202 South Sha-chong Road, Guiyang, Guizhou, China.
authors.forename: Zheng-Ming
authors.initials: ZM
authors.lastname: Liang
authors.affiliation: Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 202 South Sha-chong Road, Guiyang, Guizhou, China.
authors.forename: Xing-Hui
authors.initials: XH
authors.lastname: Wang
authors.affiliation: Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 202 South Sha-chong Road, Guiyang, Guizhou, China.
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Huang
authors.affiliation: Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 202 South Sha-chong Road, Guiyang, Guizhou, China.
authors.forename: Qi-Ji
authors.initials: QJ
authors.lastname: Li
authors.affiliation: Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 202 South Sha-chong Road, Guiyang, Guizhou, China.
authors.forename: Tian-Qi
authors.initials: TQ
authors.lastname: Guan
authors.affiliation: Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 202 South Sha-chong Road, Guiyang, Guizhou, China.
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Hao
authors.affiliation: Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 202 South Sha-chong Road, Guiyang, Guizhou, China. Electronic address: luoheng71050@aliyun.com.
authors.forename: Heng
authors.initials: H
authors.lastname: Luo
authors.affiliation: Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 202 South Sha-chong Road, Guiyang, Guizhou, China. Electronic address: gzcnp@sina.com.
authors.forename: Xiao-Sheng
authors.initials: XS
authors.lastname: Yang
mesh_terms: D000150:Acinetobacter / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D014315:Triterpenes; D009828:Oleanolic Acid; D001618:beta-Lactamases
keywords: 1α,2α-Epoxy-3β-hydroxyl oleanolic acid; Antibacterial activity; Genes expression; Synthesis