Semisynthetic aminoglycoside antibiotics: Development and enzymatic modifications.
Semisynthetic aminoglycoside antibiotics: Development and enzymatic modifications.
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DOI：
10.1007/s101560050001
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发表时间：
1999-03-01
期刊：
影响因子：
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通讯作者：
Hotta, Kunimoto
中科院分区：
文献类型：
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作者：
Kondo, S.;Hotta, Kunimoto
具有临床意义的细菌对氨基糖苷类抗生素的关键耐药机制是酶促n -乙酰化、o -磷酸化和o -核苷酸化，它们通常会导致氨基糖苷类抗生素失活。为了克服这种耐药机制，根据卡那霉素的3'- o -磷酸化，开发了第一个合理设计的半合成氨基糖苷（3',4'-双脱氧卡那霉素B）。随后，分别在卡那霉素、西索霉素和庆大霉素B的1氨基上引入(S)-4-氨基-2-羟基丁基（AHB）、乙基和(S)-3-氨基-2-羟丙基侧链，开发了阿米卡星、奈替米星和异西帕霉素。这些侧链被认为阻断了多种氨基糖苷修饰酶到达其靶位点的途径。日本临床使用的最新半合成氨基糖苷是阿贝卡星（1- n- ahb -地贝卡星），自1990年被批准作为抗耐甲氧西林金黄色葡萄球菌（MRSA）药物以来，阿贝卡星已被广泛使用。虽然它有几个可能的氨基糖苷乙酰转移酶（AACs）修饰位点，但在过去8年中出现的耐阿霉素MRSA菌株都是低或中等水平的耐药菌株，因为双功能酶AAC(6')/APH（2 '）发生率低。为了克服AAC（6’）/APH（2’）依赖性阿贝卡星耐药MRSA菌株，已经合成了2’-氨基-2’-脱氧阿贝卡星及其5-表氨基衍生物。然而，利用产氨基糖苷链霉菌菌株的AAC进行模拟修饰研究表明，AAC(3)和AAC（2’）分别将阿贝卡星转化为3’'- n -乙酰基和2’- n -乙酰基衍生物，保持了较高的抗生素活性。相反，阿米卡星（3′- n -）和地贝卡星（3- n -）同样的乙酰化导致它们失活。因此，这些新发现证实了1- n-酰基侧链的位阻作用，并阐明了阿贝卡星与其他半合成氨基糖苷不同的新方面，表明MRSA菌株即使获得了aac(3)或aac（2’）基因也不会对阿贝卡星产生耐药性。
The critical resistance mechanisms of aminoglycoside antibiotics in bacteria of clinical importance are the enzymatic N-acetylation, O-phosphorylation, and O-nucleotidylation that generally result in the inactivation of aminoglycosides. To overcome such resistance mechanisms, dibekacin (3',4'-dideoxykanamycin B) was developed as the first rationally designed semisynthetic aminoglycoside, based on the enzymatic 3'-O-phosphorylation of kanamycin. Subsequently, amikacin, netilmicin, and isepamicin were developed by introducing (S)-4-amino-2-hydroxybutyryl (AHB), ethyl, and (S)-3-amino-2-hydroxypropionyl side chains into the 1-amino group of kanamycin, sisomicin, and gentamicin B, respectively. These side chains are believed to block the access of a variety of aminoglycoside-modifying enzymes to their target sites. The latest semisynthetic aminoglycoside of clinical use in Japan is arbekacin (1-N-AHB-dibekacin), which has been extensively used since its approval as an anti-methicillin-resistant Staphylococcus aureus (MRSA) agent in 1990. Although it has several possible modification sites for aminoglycoside acetyltransferases (AACs), arbekacin-resistant MRSA strains that have emerged in the past 8 years have been those with a low or moderate level of resistance, due to a bifunctional enzyme, AAC(6')/APH(2"), at low incidence. To overcome AAC(6')/APH(2")-dependent arbekacin-resistant MRSA strains, 2"-amino-2"-deoxyarbekacin and its 5-epiamino derivative have been already synthesized. However, simulative modification studies using AACs from aminoglycoside-producing Streptomyces strains have revealed that AAC(3) and AAC(2') converted arbekacin to 3"-N-acetyl and 2'-N-acetyl derivatives, respectively, which retain high antibiotic activity. By contrast, the same acetylations of amikacin (3"-N-) and dibekacin (3-N-) resulted in their inactivation. Thus, these new findings confirmed the steric hindrance effect of the 1-N-acyl side chain and illuminated the novel aspect of arbekacin distinct from the other semisynthetic aminoglycosides, indicating that MRSA strains cannot be arbekacin-resistant even if they have acquired the aac(3) or aac(2') gene.