Antimicrobial Constituents from Machaerium Pers.: Inhibitory Activities and Synergism of Machaeriols and Machaeridiols against Methicillin-Resistant Staphylococcus aureus, Vancomycin-Resistant Enterococcus faecium, and Permeabilized Gram-Negative Pathogens

Abstract

Two new epimeric bibenzylated monoterpenes machaerifurogerol (1a) and 5-epi-machaerifurogerol (1b), and four known isoflavonoids (+)-vestitol (2), 7-O-methylvestitol (3), (+)-medicarpin (4), and 3,8-dihydroxy-9-methoxypterocarpan (5) were isolated from Machaerium Pers. This plant was previously assigned as Machaerium multiflorum Spruce, from which machaeriols A-D (6–9) and machaeridiols A-C (10–12) were reported, and all were then re-isolated, except the minor compound 9, 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 an 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 machaeriols (7 or 8) and machaeridiols (11 or 12), which exhibited a 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 the two isolates of Klebsiella pneumoniae.

Synthesis and Inhibitory Activity of Machaeridiol-Based Novel Anti-MRSA and Anti-VRE Compounds and Their Profiling for Cancer-Related Signaling Pathways

“…Based on 5,6- seco -HHDBP machaeridiols A and C ( Figure 1 ), consisting of styryl and benzopyran legends, respectively, attached to cyclic monoterpenoid via a catechol unit [ 7 , 8 , 9 ], we introduced different monoterpene units, ( R )-(−)- a -phellandrene, (−)- p -mentha-2,8-diene-1-ol [(1 R ,4 S )-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-enol], geraniol with benzopyran (stemofuran A), pinosylvin, and resveratrol legends to form new trans -benzopyan, styryl and resveratrol analogs 1 – 17 ( Scheme 1 , Scheme 2 , Scheme 3 and Scheme 4 ). Catechol and monoterpens coupling reactions were carried out using the simple and efficient one-pot synthetic protocol described by Mascal et al [ 20 ].…”

“…Based on our previous investigation on the synergistic activity between machaeridiol B and machaeriol C against MRSA [ 9 ], analogs 5 and 17 (i.e., machaeridiol type analogs) were subjected to combination studies with machaeriol C. Because both compounds 17 and machaeriol C showed potent activity against MRSA ( Table 1 and Table 2 ), they were subjected to a broth microdilution checkerboard assay [ 9 ], using an MRSA strain. The presence of machaeriol C improved the anti-MRSA activity of 17 ; for example, 17 alone showed an MIC of 0.625 μg/mL, but in combination with machaeriol C, the MIC of 17 was decreased to 0.156 μg/mL.…”

“…The examples of these phytocannabinoids are machaeriols A–D and machaeridiols A–C ( Figure 1 ), isolated from Machaerium Pers. (Rimachi 12161), which are very unique and rare in higher plants [ 7 , 8 , 9 ]. HHDBP occurs in chemotaxonomically unrelated sources, such as liverworts, which are non-vascular plants referred to as Marchantiophyta, and an aralkyl analogue of Δ 9 -tetrahydrocannabinol (THC), perrottetinen, was previously reported from the liverwort Radula perrottetii [ 10 , 11 ].…”

“…In addition, two Leguminoseae species, Desmodium canum and Sophora tetraptera , have yielded aralkyl phytocannabinoids [ 12 , 13 ]. However, we previously reported the significance of the chemistry of HHDBP or 5,6- seco -HHDBP (machaeriols and machaeridiols) and their antimicrobial activities, especially against MRSA, VRE, and Gram-negative bacteria [ 9 ]. Interestingly, the structural resemblance between machaeridiol and cannabidiol (CBD) ( Figure 1 ) reflected their similarity in antimicrobial activities against MRSA, and machaeridiols A–C were found to be more potent than cannabidiol (CBD) and vancomycin [ 9 , 14 ].…”

Special Issue: “James D. McChesney, Vision, Passion and Leadership in the Development of Plant-Derived Natural Products”

“…Muhammad et al [5] reported the identification of several antimicrobial constituents from Machaerium Pers. and their inhibitory activities and synergism against methicillinresistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and permeabilized Gram-negative pathogens.…”