TY - JOUR
T1 - T405, a New Penem, Exhibits In Vivo Efficacy against M. abscessus and Synergy with b-Lactams Imipenem and Cefditoren
AU - Rimal, Binayak
AU - Batchelder, Hunter R.
AU - Story-Roller, Elizabeth
AU - Panthi, Chandra M.
AU - Tabor, Chavis
AU - Nuermberger, Eric L.
AU - Townsend, Craig A.
AU - Lamichhane, Gyanu
N1 - Funding Information:
This study was supported by NIH awards R01 AI137329 and R01 AI155664. We have no conflicts of interest to declare.
Publisher Copyright:
Copyright © 2022 Rimal et al.
PY - 2022/6
Y1 - 2022/6
N2 - 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. 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 in vivo efficacy of T405, a recently discovered b-lactam antibiotic of the penem subclass, in a mouse model of pulmonary Mab infection. Imipenem, one of the standard-of-care drugs to treat Mab disease, and also a b-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 Mab from the onset of treatment and reduced Mab lung burden at a rate similar to that exhibited by imipenem. The MIC of T405 against Mab was unaltered after 4 weeks of exposure to T405 in the lungs of mice. Using an in vitro assay, we also demonstrate that T405 in combination with imipenem, cefditoren or avibactam exhibits synergism against Mab. 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 Mab disease.
AB - 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. 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 in vivo efficacy of T405, a recently discovered b-lactam antibiotic of the penem subclass, in a mouse model of pulmonary Mab infection. Imipenem, one of the standard-of-care drugs to treat Mab disease, and also a b-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 Mab from the onset of treatment and reduced Mab lung burden at a rate similar to that exhibited by imipenem. The MIC of T405 against Mab was unaltered after 4 weeks of exposure to T405 in the lungs of mice. Using an in vitro assay, we also demonstrate that T405 in combination with imipenem, cefditoren or avibactam exhibits synergism against Mab. 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 Mab disease.
KW - Mycobacterium abscessus
KW - Mycobacteroides abscessus
KW - T405
KW - b-lactam
KW - dual b-lactam
KW - efficacy
KW - penem
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U2 - 10.1128/aac.00536-22
DO - 10.1128/aac.00536-22
M3 - Article
C2 - 35638855
AN - SCOPUS:85132456195
SN - 0066-4804
VL - 66
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 6
ER -