In vitro antimycobacterial activities of newly synthesized benzoxazinorifamycins
In vitro antimycobacterial activities of newly synthesized benzoxazinorifamycins
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新合成苯并嗪诺福霉素的体外抗分枝杆菌活性
DOI：
10.1128/aac.35.3.542
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发表时间：
1991
影响因子：
4.9
通讯作者：
T. Hidaka
中科院分区：
文献类型：
--
作者：
H. Saito;H. Tomioka;K. Sato;M. Emori;T. Yamane;K. Yamashita;K. Hosoe;T. Hidaka
研究了新合成的利福霉素衍生物KRM-1648、KRM-1657、KRM-1668、KRM-1686和KRM-1687的体外抗分枝杆菌活性，这些衍生物具有3 ′-羟基-5 ′-（4-烷基哌嗪基）-苯并恶嗪类利福霉素的化学结构（烷基残基分别为异丁基、丙基、仲丁基、仲丁基[R构型]和仲丁基[S构型]）。通过琼脂稀释法在7 H11培养基上测定的各种致病性分枝杆菌（9个菌种，174株）90%供试菌株的代表性（KRM-1648）MIC如下（单位：微克/毫升）：结核分枝杆菌（利福平[RMP]敏感菌株），小于或等于0.0125; M.结核病（RMP耐药菌株），12.5; M. kansasii，0.05; M.海毛藻，小于或等于0.0125; M. scrofulaceum，0.1; M. avium，1.56; M. intracellulare，0.1; M.偶然地，大于100;和M.龟亚种脓肿M.龟亚种chelonae，大于100。这些值比RMP的值低64倍以上，除了对RMP抗性M的值。结核病（低8倍）和那些对快速增长，包括M。fortutuplant和M. chelonae（与RMP相同）。其他衍生物对这些分枝杆菌的体外活性水平相似。当M.在苯并恶嗪霉素（1微克/毫升）存在下培养，与向培养基中加入相同量的RMP相比，可以看到更快地杀死巨噬细胞中摄取的生物体。与添加RMP相比，添加浓度为0.05微克/毫升的苯并恶嗪类抗生素对微生物细胞内生长的抑制更为显著。KRM-1648和KRM-1657抑制M.对结核病的疗效明显优于RMP。
Newly synthesized rifamycin derivatives, KRM-1648, KRM-1657, KRM-1668, KRM-1686, and KRM-1687, having the chemical structures of 3'-hydroxy-5'-(4-alkylpiperazinyl)-benzoxazinorifamycins (alkyl residues: isobutyl, propyl, sec-butyl, sec-butyl [R configuration], and sec-butyl [S configuration], respectively), were studied for their in vitro antimycobacterial activities. Representative (KRM-1648) MICs for 90% of the strains tested, determined by the agar dilution method on 7H11 medium, of various pathogenic mycobacteria (9 species, 174 strains) were as follows (in micrograms per milliliter): Mycobacterium tuberculosis (rifampin [RMP]-susceptible strains), less than or equal to 0.0125; M. tuberculosis (RMP-resistant strains), 12.5; M. kansasii, 0.05; M. marinum, less than or equal to 0.0125; M. scrofulaceum, 0.1; M. avium, 1.56; M. intracellulare, 0.1; M. fortuitum, greater than 100; and M. chelonae subsp. abscessus and M. chelonae subsp. chelonae, greater than 100. These values are more than 64 times lower than those of RMP, except for the values against RMP-resistant M. tuberculosis (8 times lower) and those against rapid growers, including M. fortuitum and M. chelonae (the same as those of RMP). The other derivatives had similar levels of in vitro activity against these mycobacteria. When murine peritoneal macrophages in which M. intracellulare was phagocytosed in vitro were cultured in the presence of the benzoxazinorifamycins (1 microgram/ml), much more rapid killing of the organisms ingested in the macrophages was seen compared with when the same amount of RMP was added to the medium. The addition of benzoxazinorifamycins at the concentration of 0.05 micrograms/ml caused more marked suppression of intracellular growth of the organisms compared with addition of RMP. KRM-1648 and KRM-1657 inhibited intracellular growth of M. tuberculosis, and their efficacies were much greater than that of RMP.