Amino-Terminated Generation 2 Poly(amidoamine) Dendrimer as a Potential Broad-Spectrum, Nonresistance-Inducing Antibacterial Agent
Amino-Terminated Generation 2 Poly(amidoamine) Dendrimer as a Potential Broad-Spectrum, Nonresistance-Inducing Antibacterial Agent
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氨基封端的第 2 代聚（酰胺基胺）树枝状聚合物作为潜在的广谱、非耐药性诱导抗菌剂
DOI：
10.1208/s12248-012-9416-8
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
G. Sang
中科院分区：
文献类型：
--
作者：
X. Xue;Y. Wang;X. Luo;X. Chen;X. Mao;Z. Hou;Y. Zhou;H. Bai;J. Meng;F. Da;G. Sang
耐药菌败血症的治疗是临床上的一大挑战。由于传统抗生素不可避免地诱导细菌耐药性，这是许多治疗失败的原因，因此迫切需要开发新型抗生素药物。氨基封端的聚酰胺-胺树枝状大分子（PAMAM-NH 2）具有抗菌活性。然而，以前的研究集中在高世代的PAMAM-NH 2上，已经发现其表现出高毒性。本研究旨在阐明低代PAMAM-NH 2是否可用作新型抗菌剂。我们发现第2代（G2.0）PAMAM-NH 2对抗生素敏感和耐药菌株显示出显着的抗菌作用，但对人胃上皮细胞的毒性很小，并且不会诱导细菌的抗生素耐药性。扫描和透射电镜分析表明，G2.0 PAMAM-NH 2可能通过破坏细菌的细胞膜来抑制细菌的生长。G2.0 PAMAM-NH 2的给药剂量依赖性地提高了感染产超广谱β-内酰胺酶大肠杆菌（ESBL-EC）的小鼠和感染ESBL-EC和耐甲氧西林金黄色葡萄球菌组合的动物的存活率。在接种前12小时开始10 mg/kg G2.0 PAMAM-NH 2，然后在接种后0.5小时10 mg/kg的治疗方案拯救了100%的单感染小鼠和60%的多重感染小鼠。保护作用与血液中细菌滴度的降低和感染组织的形态改善有关。这些结果表明，G2.0 PAMAM-NH 2是一种潜在的广谱和非耐药性诱导的抗生素剂，具有相对较低的毒性。
The treatment of septicemia caused by antibiotic-resistant bacteria is a great challenge in the clinic. Because traditional antibiotics inevitably induce bacterial resistance, which is responsible for many treatment failures, there is an urgent need to develop novel antibiotic drugs. Amino-terminated Poly(amidoamine) dendrimers (PAMAM-NH2) are reported to have antibacterial activities. However, previous studies focused on high generations of PAMAM-NH2, which have been found to exhibit high toxicities. The present study aimed to clarify whether low generations of PAMAM-NH2 could be used as novel antibacterial agents. We found that generation 2 (G2.0) PAMAM-NH2 showed significant antibacterial effects against antibiotic-sensitive and antibiotic-resistant strains but exhibited little toxicity to human gastric epithelial cells and did not induce antibiotic resistance in bacteria. Scanning and transmission electron microscopy analyses suggested that G2.0 PAMAM-NH2 might inhibit the growth of bacteria by destroying their cell membranes. The administration of G2.0 PAMAM-NH2 dose-dependently improved the animal survival rate of mice infected with extended-spectrum beta lactamase-producing Escherichia coli (ESBL-EC) and of animals infected with a combination of ESBL-EC and methicillin-resistant Staphylococcus aureus. A treatment regimen of 10 mg/kg of G2.0 PAMAM-NH2 starting 12 h before inoculation followed by 10 mg/kg at 0.5 h after inoculation rescued 100% of singly infected mice and 60% of multiply infected mice. The protective effects were associated with the reduction of the bacterial titers in the blood and with the morphological amelioration of infected tissues. These findings demonstrate that the G2.0 PAMAM-NH2 is a potential broad-spectrum and nonresistance-inducing antibiotic agent with relatively low toxicity.
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影响因子：
10.8
作者：
Malik, N;Wiwattanapatapee, R;Duncan, R
通讯作者：
Duncan, R
DOI：
--
发表时间：
1974
期刊：
European journal of toxicology and environmental hygiene. Journal europeen de toxicologie
影响因子：
--
作者：
H. Gilles
通讯作者：
H. Gilles
DOI：
10.1126/science.1176667
发表时间：
2009-08-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fischbach MA;Walsh CT
通讯作者：
Walsh CT
影响因子：
6.2
作者：
Calabretta, Michelle K.;Kumar, Amit;Cai, Chengzhi
通讯作者：
Cai, Chengzhi
影响因子：
3.7
作者：
Wang JL;Wang JT;Chen SY;Chen YC;Chang SC
通讯作者：
Chang SC