TP-271 is a novel, fully synthetic fluorocycline antibiotic in clinical development for the treatment of respiratory infections caused by susceptible and multidrug-resistant pathogens. TP-271 was active in MIC assays against key community respiratory Gram-positive and Gram-negative pathogens, including Streptococcus pneumoniae (MIC90 = 0.03 μg/ml), methicillin-sensitive Staphylococcus aureus (MSSA; MIC90 = 0.25 μg/ml), methicillin-resistant S. aureus (MRSA; MIC90 = 0.12 μg/ml), Streptococcus pyogenes (MIC90 = 0.03 μg/ml), Haemophilus influenzae (MIC90 = 0.12 μg/ml), and Moraxella catarrhalis (MIC90 ≤0.016 μg/ml). TP-271 showed activity (MIC90 = 0.12 μg/ml) against community-acquired MRSA expressing Panton- Valentine leukocidin (PVL). MIC90 values against Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae were 0.004, 1, and 4 μg/ml, respectively. TP-271 was efficacious in neutropenic and immunocompetent animal pneumonia models, generally showing, compared to the burden at the start of dosing, ~2 to 5 log10 CFU reductions against MRSA, S. pneumoniae, and H. influenzae infections when given intravenously (i.v.) and ~1 to 4 log10 CFU reductions when given orally (p.o.). TP-271 was potent against key community-acquired bacterial pneumonia (CABP) pathogens and was minimally affected, or unaffected, by tetracycline-specific resistance mechanisms and fluoroquinolone or macrolide drug resistance phenotypes.