Fluorocycline TP-271 Is Potent against Complicated Community-Acquired Bacterial Pneumonia Pathogens

Abstract

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

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Francisella tularensis SCHU S4 Infection in BALB/c Mice and Cynomolgus Macaques

“…and oral therapies for the treatment of tularemia in both contained and mass-casualty settings (2), the threat of bioterrorist use of engineered drug-resistant biothreat pathogens has prompted the development of new countermeasures with potency against these highly virulent organisms. TP-271 is a novel fluorocycline antibiotic which retains in vitro activity against multidrug-resistant Gram-positive and Gram-negative pathogens, including those expressing the most common tetracycline-specific efflux and ribosome protection mechanisms (19). In the present study, TP-271 was active in vitro against F. tularensis, a pathogen that could be used as a bioweapon during a terrorist attack.…”

“…TP-271 was efficacious in mouse models of pneumonia challenged with tetracyclineresistant bacterial community-acquired respiratory pathogens (19). In the present proof-of-concept studies in mice and NHPs, TP-271 was efficacious against inhalational tularemia when administered before (PEP; mouse only) and after (Tx; mouse and NHP) the onset of symptoms, with little or no relapse following the end of dosing.…”

“…TP-271 is a novel fluorocycline antibiotic currently in phase 1 clinical trials, and development is planned for oral and intravenous treatment of moderate to severe community-acquired bacterial pneumonia caused by susceptible and drug-resistant public health pathogens and other serious respiratory bacterial infections, including those caused by biothreat pathogens (15)(16)(17). These studies assessed the nonclinical efficacy of TP-271 utilizing postexposure prophylaxis and therapeutic treatment models of inhalational tularemia in mice and a therapeutic treatment model of inhalational tularemia in the cynomolgus macaque.…”

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

“…[322,323] Compared to eravacycline,itshows improved activity against carbapenem-resistant Enterobacteriaceae, A. baumannii,and P. aeruginosa. Notably,TP-6076 represents the most active tetracycline against Pseudomonas discovered to date.T wo additional tetracycline derivatives,KBP-7072 [324] (structure unknown) and TP-271, [325] are in phase Ia nd are directed at Gram-positive respiratory pathogens,a mong others. Angewandte Chemie Reviews 5.6.…”

Fighting bacterial resistance: approaches, challenges, and opportunities in the search for new antibiotics.Part 1. Antibiotics used in clinical practice: mechanisms of action and the development of bacterial resistance

“…31), described recently by Grossman et al [70], demonstrates high in vitro potency against multidrug-resistant bacteria. These results once more show that changing the antibiotic's structure is a promising approach to combat bacterial resistance.…”