In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936)
In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936)
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DOI：
10.1128/aac.43.4.738
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发表时间：
1999-04-01
影响因子：
4.9
通讯作者：
Testa, RT
中科院分区：
文献类型：
--
作者：
Petersen, PJ;Jacobus, NV;Testa, RT
米诺环素的9-t-丁基甘酰基氨基衍生物（ttbg - mino）是最近合成的一种新型抗生素-甘四环素的成员，这种新的衍生物，像第一个甘四环素，米诺环素的N，N-二甲基甘酰基氨基衍生物和6-去甲基-6-脱氧四环素一样，具有抗含有导致四环素耐药的两个主要决定因素的细菌分离物的活性：核糖体保护和主动外排。研究了TBG-MINO和比较剂对具有四环素耐药性的菌株的体外活性，以及近期临床好氧和厌氧革兰氏阳性和革兰氏阴性菌的体外活性。TBG-MINO的MIC范围为0.25 ~ 0.5 μ g/ml，对表达tet(M)（核糖体保护）、tet(A)、tet(B)、tet(C)、tet(D)和tet(K)（外排耐药决定因素）的菌株具有良好的活性，对耐甲氧西林金黄色葡萄球菌（MRSA）、耐青霉素链球菌和耐万古霉素肠球菌（MIC为90%的菌株被抑制，小于或等于0.5 μ g/ml）具有相似的活性。TBG-MINO对多种革兰氏阴性需氧和厌氧细菌均有抑制作用，其中大多数细菌对四环素和二甲胺四环素不敏感。TBG-MINO在小鼠体内对大肠杆菌、金黄色葡萄球菌和肺炎链球菌引起的急性致死性感染有保护作用。经静脉给药的TBG-MINO对金黄色葡萄球菌（包括MRSA）引起的感染有效。ttg - mino对四环素敏感的大肠杆菌菌株以及含有tet(K)或tct(M)抗性决定因素的菌株（中位有效剂量[ED(50)s]， 0.79至2.3 mg/kg体重）以及含有et(M)或外排决定因素tet(A), tet(B)或tet(C)的大肠杆菌菌株（ED(50)s， 1.5至3.5 mg/kg）引起的感染有效。TBG-MINO对广泛的革兰氏阳性和革兰氏阴性需氧和厌氧细菌具有抗菌活性，包括对其他化疗药物耐药的菌株。TBG-MINO的体内保护作用，特别是对耐药菌感染的保护作用，与体外活性一致。
The 9-t-butylglycylamido derivative of minocycline (TBG-MINO) is a recently synthesized member of a novel group of antibiotics, the glycylcyclines, This new derivative, like the first glycylcyclines, the N,N-dimethylglycylamido derivative of minocycline and 6-demethyl-6-deoxytetracycline, possesses activity against bacterial isolates containing the two major determinants responsible for tetracycline resistance: ribosomal protection and active efflux. The in vitro activities of TBG-MINO and the comparative agents were evaluated against strains with characterized tetracycline resistance as well as a spectrum of recent clinical aerobic and anaerobic gram-positive and gram-negative bacteria. TBG-MINO, with an MIC range of 0.25 to 0.5 mu g/ml, showed good activity against strains expressing tet(M) (ribosomal protection), fet(A), tet(B), tet(C), tet(D), and tet(K) (efflux resistance determinants), TBG-MINO exhibited similar activity against methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant streptococci, and vancomycin-resistant enterococci (MICs at which 90% of strains are inhibited, less than or equal to 0.5 mu g/ml). TBG-MINO exhibited activity against a wide diversity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to tetracycline and minocycline, The in vivo protective effects of TBG-MINO were examined against acute lethal infections in mice caused by Escherichia coli, S. aureus, and Streptococcus pneumoniae isolates. TBG-MINO, administered intravenously, demonstrated efficacy against infections caused by S, aureus including MRSA. strains and strains containing tet(K) or tct(M) resistance determinants (median effective doses [ED(50)s], 0.79 to 2.3 mg/kg of body weight), TBG-MINO demonstrated efficacy against infections caused by tetracycline-sensitive E. coli strains as well as E. coli strains containing either et(M) or the efflux determinant tet(A), tet(B), or tet(C) (ED(50)s, 1.5 to 3.5 mg/kg), Overall, TBG-MINO shows antibacterial activity against a wide spectrum of gram-positive and gram-negative aerobic and anaerobic bacteria including strains resistant to other chemotherapeutic agents. The in vivo protective effects, especially against infections caused by resistant bacteria, corresponded with the in vitro activity of TBG-MINO.