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

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