T405, a New Penem, Exhibits In Vivo Efficacy against M. abscessus and Synergy with β-Lactams Imipenem and Cefditoren.
T405, a New Penem, Exhibits In Vivo Efficacy against M. abscessus and Synergy with β-Lactams Imipenem and Cefditoren.
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DOI：
10.1128/aac.00536-22
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发表时间：
2022-06-21
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
--
作者：
结核分枝杆菌是一种新出现的环境微生物，可导致肺功能受损患者的慢性肺病，如囊性纤维化和支气管扩张。它本质上对大多数抗生素具有耐药性，因此只有少数抗生素可以重新用于治疗Mab疾病。虽然目前的建议要求每天摄入多种抗生素超过一年，但治愈率很低，而且往往与严重的不良事件有关。在此，我们描述了T405（一种最近发现的青霉烯亚类β-内酰胺抗生素）在肺单抗感染小鼠模型中的体内疗效。亚胺培南是治疗Mab疾病的标准治疗药物之一，也是一种与T405相似的化学类别的β-内酰胺抗生素，被纳入作为对照药物。丙磺舒与T405和亚胺培南一起使用，以降低其肾清除率。T405从治疗开始就表现出对Mab的杀菌活性，并以与亚胺培南相似的速率降低Mab肺负荷。在小鼠肺中暴露于T405 4周后，T405对Mab的MIC没有改变。使用体外试验，我们还证明了T405与亚胺培南、头孢妥仑或阿维巴坦组合对单克隆抗体具有协同作用。此外，我们描述了一种在工业规模上合成和纯化T405的方案。这些属性使T405成为进一步临床前评估以治疗Mab疾病的有希望的候选物。
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 β-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 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 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.
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影响因子：
10
作者：
Floto RA;Olivier KN;Saiman L;Daley CL;Herrmann JL;Nick JA;Noone PG;Bilton D;Corris P;Gibson RL;Hempstead SE;Koetz K;Sabadosa KA;Sermet-Gaudelus I;Smyth AR;van Ingen J;Wallace RJ;Winthrop KL;Marshall BC;Haworth CS;US Cystic Fibrosis Foundation and European Cystic Fibrosis Society
通讯作者：
US Cystic Fibrosis Foundation and European Cystic Fibrosis Society
DOI：
10.1016/j.ijid.2021.01.062
发表时间：
2021-03
期刊：
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases
影响因子：
--
作者：
Gumbo T;Sherman CM;Deshpande D;Alffenaar JW;Srivastava S
通讯作者：
Srivastava S
影响因子：
5.3
作者：
Gupta R;Al-Kharji NMSA;Alqurafi MA;Nguyen TQ;Chai W;Quan P;Malhotra R;Simcox BS;Mortimer P;Brammer Basta LA;Rohde KH;Buynak JD
通讯作者：
Buynak JD
DOI：
10.1107/s0907444913013085
发表时间：
2013-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Correale, Stefania;Ruggiero, Alessia;Berisio, Rita
通讯作者：
Berisio, Rita
DOI：
10.1107/s0907444912049268
发表时间：
2013-03-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Both, Dominic;Steiner, Eva Maria;Schneider, Gunter
通讯作者：
Schneider, Gunter