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 (MIC 90 ϭ 0.03 g/ml), methicillin-sensitive Staphylococcus aureus (MSSA; MIC 90 ϭ 0.25 g/ml), methicillin-resistant S. aureus (MRSA; MIC 90 ϭ 0.12 g/ml), Streptococcus pyogenes (MIC 90 ϭ 0.03 g/ml), Haemophilus influenzae (MIC 90 ϭ 0.12 g/ml), and Moraxella catarrhalis (MIC 90 Յ0.016 g/ml). TP-271 showed activity (MIC 90 ϭ 0.12 g/ml) against community-acquired MRSA expressing PantonValentine leukocidin (PVL). MIC 90 values against Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae were 0.004, 1, and 4 g/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 log 10 CFU reductions against MRSA, S. pneumoniae, and H. influenzae infections when given intravenously (i.v.) and~1 to 4 log 10 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. IMPORTANCE Rising resistance rates for macrolides, fluoroquinolones, and -lactams in the most common pathogens associated with community-acquired bacterial pneumonia (CABP) are of concern, especially for cases of moderate to severe infections in vulnerable populations such as the very young and the elderly. New antibiotics that are active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus are needed for use in the empirical treatment of the most severe forms of this disease. TP-271 is a promising new fluorocycline antibiotic demonstrating in vitro potency and nonclinical efficacy by intravenous and oral administration against the major pathogens associated with moderate to severe CABP.KEYWORDS TP-271, community-acquired bacterial pneumonia, fluorocycline C ommunity-acquired bacterial pneumonia (CABP) is a serious condition associated with mortality rates estimated to be as high as 12 to 14% for hospitalized individuals and 25 to 40% for those admitted to intensive care units (1-3). Lower respiratory tract infections were the second greatest cause of deaths and years of life lost in 2013 as reported by The Global Burden of Disease Study, with the highest incidence occurring in children Ͻ5 years and adults Ͼ65 years (1, 4). The Centers for Disease
