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

• Main Authors: Ilias Muhammad, Melissa R. Jacob, Mohamed A. Ibrahim, Vijayasankar Raman, Mallika Kumarihamy, Mei Wang, Taha Al-Adhami, Charlotte Hind, Melanie Clifford, Bethany Martin, Jianping Zhao, J. Mark Sutton, Khondaker Miraz Rahman
• Format: Article
• Language: English
• Published: MDPI AG 2020-12-01
• Series: Molecules
• Subjects: <i>Machaerium</i> Rimachi 12161; machaerifurogerol; 5-<i>epi</i>-machaerifurogerol; machaeriol A–C; machaeridiol A–C; isoflavonoid
• Online Access: https://www.mdpi.com/1420-3049/25/24/6000
• ISSN: 1420-3049

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