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

Abstract

Mycobacteroides abscessus ( Mab ) 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 Mab disease.

Strongly Bactericidal All-Oral β-Lactam Combinations for the Treatment of Mycobacterium abscessus Lung Disease

“…Different classes of β-lactams, and different members within a class, differentially inhibit the numerous M. abscessus transpeptidases and other enzymes involved in peptidoglycan synthesis ( 12 – 17 ). Thus, multiple recent reports have demonstrated the potential of combining two β-lactams to achieve additive and synergistic effects in vitro ( 18 – 22 ) as well as in vivo ( 23 ).…”

Mycobacterium abscessus: It’s Complex

“…Another promising drug candidate for use against M. abscessus is T405, which is a novel b-lactam of the penem subclass and was recently shown to have in vitro synergy in combination with other antibiotics, including imipenem cefditoren or avibactam [ 141 ]. Furthermore, T405 combined with probenecid exhibited bactericidal efficacy in the C3HeB/FeJ in vivo mouse model against the well-characterized ATCC29977 reference strain (Rimal B. et al, AAC, 2022, PMID:35638855).…”

“…Ganapathy et al have recently shown that a novel mycobacterial DNA gyrase inhibitor (MGI), an advanced M. tb drug candidate, EC/11716, has in vitro bactericidal activity against both Mav and M. abscessus and importantly has activity against M. abscessus biofilms [140]. EC/11716 was also shown to have in vivo efficacy in a preclinical M. abscessus NOD SCID mouse model [140] Another promising drug candidate for use against M. abscessus is T405, which is a novel b-lactam of the penem subclass and was recently shown to have in vitro synergy in combination with other antibiotics, including imipenem cefditoren or avibactam [141]. Furthermore, T405 combined with probenecid exhibited bactericidal efficacy in the C3HeB/FeJ in vivo mouse model against the well-characterized ATCC29977 reference strain (Rimal B. et al, AAC, 2022, PMID:35638855).…”

Structure–Activity Relationship of Penem Antibiotic Side Chains Used against Mycobacteria Reveals Highly Active Compounds

“…A new penem, T405 , was identified from an antibiotic screen against Mtb and showed strong antimicrobial activity against laboratory strains of Mtb and Mab , as well as a panel of 20 clinical isolates of Mab . Moreover, T405 was found efficacious in treating Mab pulmonary infection in an in vivo model . While T405 utilizes the penem pharmacophore, the side-chain branching from C2 gives the drug its unique properties (Scheme ).…”