TY - JOUR
T1 - Fluorocycline TP-271 is potent against complicated community-acquired bacterial pneumonia pathogens
AU - Grossman, Trudy H.
AU - Fyfe, Corey
AU - O'Brien, William
AU - Hackel, Meredith
AU - Minyard, Mary Beth
AU - Waites, Ken B.
AU - Dubois, Jacques
AU - Murphy, Timothy M.
AU - Slee, Andrew M.
AU - Weiss, William J.
AU - Sutcliffe, Joyce A.
N1 - Funding Information:
We acknowledge the contributions from the Tetraphase Chemistry Department for the synthesis of TP-271 for these studies and appreciate the support of Anne Radcliff and Katie Edwards at CUBRC. Technical support from Donna M. Crabb for Mycoplasma pneumoniae MIC assays is gratefully acknowledged. Tetraphase Pharmaceuticals is also grateful to the late Donald Low for his support of the TP-271 program and the testing of TP-271 against isolates from the Canadian Bacterial Surveillance Network. These studies were funded in part by NIAID Partnership grant 1R01AI093484-01 and NIAID contract HHSN272201100028C awarded to CUBRC and Tetraphase Pharmaceuticals. Trudy Grossman, Corey Fyfe, William O'Brien, and Joyce Sutcliffe were employees of Tetraphase Pharmaceuticals at the time that this work was performed
Publisher Copyright:
© 2017 Grossman et al.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
KW - Community-acquired bacterial pneumonia
KW - Fluorocycline
KW - TP-271
UR - http://www.scopus.com/inward/record.url?scp=85031426219&partnerID=8YFLogxK
U2 - 10.1128/mSphere.00004-17
DO - 10.1128/mSphere.00004-17
M3 - Article
AN - SCOPUS:85031426219
VL - 2
JO - mSphere
JF - mSphere
SN - 2379-5042
IS - 1
M1 - e00004-17
ER -