Phenanthrene Antibiotic Targets Bacterial Membranes and Kills <italic>Staphylococcus aureus</italic> With a Low Propensity for Resistance Development.

New classes of antibiotics with different mechanisms of action are urgently required for combating antimicrobial resistance. Blestriacin, a dihydro-biphenanthrene with significant antibacterial activity, was recently isolated from the fibrous roots of <italic>Bletilla striata</italic>. Here, we report the further characterization of the antimicrobial potential and mode of action of blestriacin. The phenanthrene compound inhibited the growth of all tested clinical isolates of <italic>Staphylococcus aureus</italic> including methicillin-resistant <italic>S. aureus</italic> (MRSA). The minimum inhibitory concentrations (MICs) of blestriacin against these pathogens ranged from 2 to 8 μg/mL. Minimum bactericidal concentration (MBC) tests were conducted, and the results demonstrated that blestriacin was bactericidal against <italic>S. aureus</italic>. This effect was confirmed by the time-kill assays. At bactericidal concentrations, blestriacin caused loss of membrane potential in <italic>B. subtilis</italic> and <italic>S. aureus</italic> and disrupted the bacterial membrane integrity of the two strains. The spontaneous mutation frequency of <italic>S. aureus</italic> to blestriacin was determined to be lower than 10^-9. The selection and whole genome sequencing of the blestriacin –resistant mutants of <italic>S. aureus</italic> indicated that the development of blestriacin resistance in <italic>S. aureus</italic> involves mutations in multi-genes. All these observations can be rationalized by the suggestion that membrane is a biological target of blestriacin. [ABSTRACT FROM AUTHOR]