TY - JOUR
T1 - Development of a penem antibiotic against Mycobacteroides abscessus
AU - Batchelder, Hunter R.
AU - Story-Roller, Elizabeth
AU - Lloyd, Evan P.
AU - Kaushik, Amit
AU - Bigelow, Kristina M.
AU - Maggioncalda, Emily C.
AU - Nuermberger, Eric L.
AU - Lamichhane, Gyanu
AU - Townsend, Craig A.
N1 - Funding Information:
This study was supported by NIH research grant R01AI137329 to C.A.T., E.L.N., and G.L. and Pearl M. Stetler Fund Research Award to E.S.-R. We acknowledge Johns Hopkins University Core Coins to G.L. to support drug level determination reported in pharmacokinetics studies.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - β-lactams are the most widely used antibiotic class to treat bacterial infections in humans. Mycobacteroides abscessus is an emerging pulmonary pathogen resistant to most antibiotics, including penicillins and cephalosporins. With no current FDA-approved treatment and cure rates <50%, there is a pressing need for effective therapies. Here we report T405, a new β-lactam of the penem subclass that exhibits potent activity against M. abscessus and a panel of drug-resistant strains isolated from cystic fibrosis patients. Additionally, in combination with the β-lactamase inhibitor avibactam, the rate of spontaneous resistance of M. abscessus to T405 approached the limit of detection. Lastly, we show the favorable pharmacokinetic profile of T405 in mice and the absence of toxicity at elevated dosage, which support the clinical potential of this compound.
AB - β-lactams are the most widely used antibiotic class to treat bacterial infections in humans. Mycobacteroides abscessus is an emerging pulmonary pathogen resistant to most antibiotics, including penicillins and cephalosporins. With no current FDA-approved treatment and cure rates <50%, there is a pressing need for effective therapies. Here we report T405, a new β-lactam of the penem subclass that exhibits potent activity against M. abscessus and a panel of drug-resistant strains isolated from cystic fibrosis patients. Additionally, in combination with the β-lactamase inhibitor avibactam, the rate of spontaneous resistance of M. abscessus to T405 approached the limit of detection. Lastly, we show the favorable pharmacokinetic profile of T405 in mice and the absence of toxicity at elevated dosage, which support the clinical potential of this compound.
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U2 - 10.1038/s42003-020-01475-2
DO - 10.1038/s42003-020-01475-2
M3 - Article
C2 - 33288821
AN - SCOPUS:85097280936
SN - 2399-3642
VL - 3
JO - Communications biology
JF - Communications biology
IS - 1
M1 - 741
ER -