Description: Sarecycline (formerly known as WC-3035 and P005672; trade name: Seysara) is the first narrow spectrum tetracycline-class antibiotic being developed for acne treatment. In Oct 2018, FDA approved Sarecycline for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older. In addition to exhibiting activity against important skin/soft tissue pathogens, sarecycline exhibits targeted antibacterial activity against clinical isolates of Cutibacterium acnes 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 normal human intestinal microbiome. Also, reduced activity against Escherichia coliwas observed in vivo in a murine septicemia model with PD50 values at >40 mg/kg and 5.72 mg/kg for sarecycline and doxycycline, respectively. Sarecycline was also 4 to 8-fold less active against representative anaerobic bacteria that also comprise normal human intestinal microbiome. Additionally, sarecycline displayed a low propensity for resistance development in C. acnes strains, with spontaneous mutation frequencies of 10-10 at 4 to 8-times the MIC, similar to minocycline and vancomycin. When tested against Gram-positive pathogens with defined tetracycline resistance mechanisms, sarecycline was more active than tetracycline against the tet(K) and tet(M) strains, with MIC ranging from 0.125 to 1.0 ug/mL and 8 ug/mL, respectively, compared with 16 to 64 ug/mL and 64 ug/mL for tetracycline, respectively. However, sarecycline activity in the tet(K) and tet(M) strains were decreased compared to wildtype, which demonstrated MIC ranging from 0.06 to 0.25 ug/mL, though not as pronounced as tetracycline.