T405, a New Penem, Exhibits In Vivo Efficacy against M. abscessus and Synergy with β-Lactams Imipenem and Cefditoren

Mycobacteroides abscessus ( ) is an emerging environmental microbe that causes chronic lung disease in patients with compromised lung function such as cystic fibrosis and bronchiectasis. It is intrinsically resistant to most antibiotics, therefore there are only few antibiotics that can be repurposed to treat disease. Although current recommendations require daily intake of multiple antibiotics for more than a year, cure rate is low and often associated with significant adverse events. Here, we describe efficacy of T405, a recently discovered β-lactam antibiotic of the penem subclass, in a mouse model of pulmonary infection. Imipenem, one of the standard-of-care drugs to treat disease, and also a β-lactam antibiotic from a chemical class similar to T405, was included as a comparator. Probenecid was included with both T405 and imipenem to reduce the rate of their renal clearance. T405 exhibited bactericidal activity against from the onset of treatment and reduced lung burden at a rate similar to that exhibited by imipenem. The MIC of T405 against was unaltered after 4 weeks of exposure to T405 in the lungs of mice. Using an assay, we also demonstrate that T405 in combination with imipenem, cefditoren or avibactam exhibits synergism against . Additionally, we describe a scheme for synthesis and purification of T405 on an industrial scale. These attributes make T405 a promising candidate for further preclinical assessment to treat disease.