Development of a penem antibiotic against Mycobacteroides abscessus

• Published in: Communications biology Vol. 3; no. 1; p. 741
• Main Authors: Batchelder, Hunter R., Story-Roller, Elizabeth, Lloyd, Evan P., Kaushik, Amit, Bigelow, Kristina M., Maggioncalda, Emily C., Nuermberger, Eric L., Lamichhane, Gyanu, Townsend, Craig A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-12-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/309; 631/326/22; Antibiotics; Biology; Biomedical and Life Sciences; Cephalosporins; Clinical isolates; Cystic fibrosis; Drug resistance; Life Sciences; Patients; Pharmacokinetics; Toxicity; β Lactamase; β-Lactam antibiotics
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-020-01475-2

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.
Batchelder et al. report a new penem class antibiotic, T405, which exhibits potent activity against
M. abscessus
and clinical isolates from cystic fibrosis patients. The development of resistance to T405 is inhibited with the addition of a β-lactamase inhibitor, avibactam. Its clinical potential is further demonstrated by T405 displaying a favourable pharmacokinetic profile in mice with an absence of toxicity.