Antimicrobial constituents from Machaerium Pers.: Inhibitory activities and synergism of machaeriols and machaeridiols against methicillin-resistant Staphylococcus aureus and Vancomycin-resistant Enterococcus faecium and perm

Authors: MUHAMMAD, ILIAS - University Of Mississippi; JACOB, MELISSA - University Of Mississippi; IBRAHIM, MOHAMED - University Of Mississippi; RAMAN, VIJAYSANKAR - University Of Mississippi; KUMARIHAMY, MALLIKA - University Of Mississippi; Wang, Mei; AL-ADHAMI, TAHA - King'S College; HIND, CHARLOTTE - Public Health England (PHE); CLIFFORD, MELANIE - Public Health England (PHE); MARTIN, BETHANY - Public Health England (PHE); SUTTON, MARK - Public Health England (PHE); RAHMAN, MIRAZ - King'S College; ZHAO, JIANPING - University Of Mississippi

Submitted to: Molecules
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/16/2020
Publication Date: 12/18/2020
Citation: Muhammad, I., Jacob, M.R., Ibrahim, M.A., Raman, V., Kumarihamy, M., Wang, M., Al-Adhami, T., Hind, C., Clifford, M., Martin, B., Sutton, M., Rahman, M., Zhao, J. 2020. Antimicrobial constituents from Machaerium Pers.: Inhibitory activities and synergism of machaeriols and machaeridiols against methicillin-resistant Staphylococcus aureus and Vancomycin-resistant Enterococcus faecium and perm. Molecules. 25/6000. https://doi.org/10.3390/molecules25246000.
DOI: https://doi.org/10.3390/molecules25246000

Interpretive Summary: The genus Machaerium Pers. (Fabaceae) consists of approximately 130 species, and several species of this genus are used in traditional medicines and considered to have multiple medicinal properties. Earlier studies on one of the Machaerium species (Manuel Rimachi, Y. - 12161), named M. multiflorum Spruce (this species should be treated as an unidentified species of Machaerium Pers. as determined by collection information), have yielded four unique (+)-trans-hexahydrodibenzopyrans (HHDBP), machaeriol A-D, and three 5,6-seco-HHDBPs, machaeridiol A-C. These are the first reported novel phyto-cannabinoids from a higher plant other than Cannabis. The significance of the chemistry and biological activity of these aralkyl class of cannabinoid-type compounds showed significant enhancement of antimicrobial activity against various strains of methicillin-resistant Staphylococus aureus (MRSA) and vancomycin resistant Enterococci (VRE).

Technical Abstract: Two new epimeric bibenzylated monoterpenes machaerifurogerol (1a) and 5-epi- machaerifurogerol (1b), and four known flavonoids (+)-vestitol (2), 7-O-methylvestitol (3), (+)-medicarpin (4) and 3,8-dihydroxy-9-methoxypterocarpan (5) were isolated from Machaerium Pers. This plant had previously been assigned as M. multiflorum Spruce., from which machaeriol A-D (6-9) and machaeridiol A-C (10-12) were reported, and now re-isolated for a comprehensive antimicrobial activity evaluation. Structures of the isolated compounds were determined by full NMR and mass spectroscopic data. Among the isolated compounds, the mixture 10+11 was the most active with MIC value of 1.25 µg/mL against methicillin-resistant Staphylococcus aureus (MRSA) strains BAA 1696, -1708, -1717, -33591, and vancomycin-resistant Enterococcus faecium (VRE 700221) and E. faecalis (VRE 51299) and vancomycin-sensitive E. faecalis (VSE 29212). Compounds 6-8 and 10-12 were found to be more potent against MRSA 1708, and 6, 11 and 12 against VRE 700221, than the drug control ciprofloxacin and vancomycin. A combination study using an in vitro Checkerboard method was carried out for machaeriol (7 or 8) and machaeridiol (11 or 12) exhibited strong synergistic activity of 12+8 (MIC 0.156 and 0.625 µg/ml), with >32- and >8- fold reduction of MIC’s, compared to 12, against MRSA 1708 and -1717, respectively. In the presence of sub-inhibitory concentrations on polymyxin B nonapeptide (PMBN), compounds 10+11, 11, 12 and 8 showed activity in the range of 0.5 – 8 µg/ml for two strains of Acinetobacter baumannii, 2 – 16 µg/ml against Pseudomonas aeruginosa PAO1 and 2 µg/ml against Escherichia coli NCTC 12923, but were inactive (MIC >64 µg/ml) against two isolates of Klebsiella pneumoniae.