title: In vivo efficacy and toxicity studies of a novel antibacterial agent: 14-o-[(2-amino-1,3,4-thiadiazol-5-yl)thioacetyl] mutilin.
abstract: A new pleuromutilin derivative with excellent antibacterial activity, 14-O-[(2-amino-1,3,4-thiadiazol-5-yl) thioacetyl] mutilin (ATTM), may serve as a possible lead compound for the development of antibacterial drugs. However, in vivo efficacy and toxicity evaluations of this compound have not been performed. In this study, we evaluated the efficacy of ATTM by measuring the survival of mice after a lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA), and the 50% effective dose (ED50) was 5.74 mg/kg by the intravenous route. In an oral single-dose toxicity study, ATTM was orally administered to mice at different doses and the 50% lethal dose (LD50) was calculated to be 2304.4 mg/kg by the Bliss method. The results of the subchronic oral toxicity study in rats showed no mortality, exterior signs of toxicity, or differences in the total weight gain or relative organ weights between the treated groups and control group after administration. The hematological and serum biochemical data showed no differences between the treated and control groups, except for the levels of alkaline phosphatase (ALP), creatinine (CR) and blood glucose (GLU), which were significantly different in the high-dose group. The differences in the histopathological findings between the treated groups and the control group were not considered to be treatment-related. Our results indicated that the no observed adverse effect level (NOAEL) for ATTM was 5 mg/kg in this study.
authors: Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China. YJL.BZN@163.com.
authors: Chao
authors: C
authors: Zhang
authors: Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China. yiyp2015@163.com.
authors: Yunpeng
authors: Y
authors: Yi
authors: Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China. chenjiongran@126.com.
authors: Jiongran
authors: J
authors: Chen
authors: Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China. renshengxin0824@163.com.
authors: Rensheng
authors: R
authors: Xin
authors: Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China. yz19890502@126.com.
authors: Zhen
authors: Z
authors: Yang
authors: Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China. guozhiting197998@163.com.
authors: Zhiting
authors: Z
authors: Guo
authors: Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China.
authors: Jianping
authors: J
authors: Liang
authors: Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China. shangrf1974@163.com.
authors: Ruofeng
authors: R
authors: Shang
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D004224:Diterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007928:Lethal Dose 50; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity*; D051379:Mice; D019055:No-Observed-Adverse-Effect Level; D011083:Polycyclic Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality* / Q000662:veterinary; D023382:Toxicity Tests, Acute; D000097567:Pleuromutilins
chemical_list: D000900:Anti-Bacterial Agents; D004224:Diterpenes; D011083:Polycyclic Compounds; D000097567:Pleuromutilins