Sarecycline is the first narrow-spectrum tetracycline-class antibiotic being developed for acne treatment. In addition to exhibiting activity against important skin/soft tissue pathogens, sarecycline exhibits targeted antibacterial activity against clinical isolates of In the current study, sarecycline was 16- to 32-fold less active than broad-spectrum tetracyclines-such as minocycline and doxycycline-against aerobic Gram-negative bacilli associated with the normal human intestinal microbiome. Also, reduced activity against was observed in a murine septicemia model, with the 50% protective doses, or the doses required to achieve 50% survival, being >40 mg/kg of body weight and 5.72 mg/kg for sarecycline and doxycycline, respectively. Sarecycline was also 4- to 8-fold less active than doxycycline against representative anaerobic bacteria that also comprise the normal human intestinal microbiome. Additionally, strains displayed a low propensity for the development of resistance to sarecycline, with spontaneous mutation frequencies being 10 at 4 to 8 times the MIC, similar to those for minocycline and vancomycin. When tested against Gram-positive pathogens with defined tetracycline resistance mechanisms, sarecycline was more active than tetracycline against (K) and (M) strains, with MICs ranging from 0.125 to 1.0 μl/ml and 8 μl/ml, respectively, compared with MICs of 16 to 64 μl/ml and 64 μl/ml for tetracycline, respectively. However, sarecycline activity against the (K) and (M) strains was decreased compared to that against the wild type, which demonstrated MICs ranging from 0.06 to 0.25 μl/ml, though the decrease in the activity of sarecycline against the (K) and (M) strains was not as pronounced as that of tetracycline. These findings support sarecycline as a narrow-spectrum tetracycline-class antibiotic that is effective for the treatment of acne, and further investigation into the potential reduced effects on the gut microbiome compared with those of other agents is warranted.