Expanding the Spectrum of Antibiotics Capable of Killing Multidrug-ResistantStaphylococcus aureusandPseudomonas aeruginosa
Expanding the Spectrum of Antibiotics Capable of Killing Multidrug-ResistantStaphylococcus aureusandPseudomonas aeruginosa
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DOI：
10.1002/cmdc.202000239
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发表时间：
2020-06-26
期刊：
影响因子：
3.4
通讯作者：
Rice, Charles V.
中科院分区：
文献类型：
--
作者：
Lam, Anh K.;Panlilio, Hannah;Rice, Charles V.
耐药金黄色葡萄球菌和铜绿假单胞菌的感染是一个严重的威胁，因为抗生素效力的降低使许多患者的治疗决定复杂化，并延长了疾病状态。为了扩大抗菌素耐药(AMR)病原菌的治疗手段，600-Da支化聚乙烯亚胺(BPEI)可以克服抗生素耐药机制，增强β-内酰胺类抗生素对革兰氏阳性菌的抗药性。BPEI与细胞壁磷壁酸结合，并使青霉素结合蛋白PBP2a和PBP4的耐药因子失效。这项研究描述了一种新的增强BPEI的作用机制，抗生素通常被认为对革兰氏阳性菌有效，但对革兰氏阴性菌无效。600-Da BPEI能够减少药物内流的障碍，并促进针对细胞内机制的非β-内酰胺类共用药物红霉素的吸收。此外，BPEI还可以抑制人上皮角质形成细胞产生细胞因子IL-8。这使BPEI能够发挥广谱抗生素增强剂的作用，并扩大了改进药物设计、抗生素开发和针对病原菌的治疗方法的机会，特别是在伤口护理方面。
Infections from antibiotic-resistantStaphylococcus aureusandPseudomonas aeruginosaare a serious threat because reduced antibiotic efficacy complicates treatment decisions and prolongs the disease state in many patients. To expand the arsenal of treatments against antimicrobial-resistant (AMR) pathogens, 600-Da branched polyethylenimine (BPEI) can overcome antibiotic resistance mechanisms and potentiate beta-lactam antibiotics against Gram-positive bacteria. BPEI binds cell-wall teichoic acids and disables resistance factors from penicillin binding proteins PBP2a and PBP4. This study describes a new mechanism of action for BPEI potentiation of antibiotics generally regarded as agents effective against Gram-positive pathogens but not Gram-negative bacteria. 600-Da BPEI is able to reduce the barriers to drug influx and facilitate the uptake of a non-beta-lactam co-drug, erythromycin, which targets the intracellular machinery. Also, BPEI can suppress production of the cytokine interleukin IL-8 by human epithelial keratinocytes. This enables BPEI to function as a broad-spectrum antibiotic potentiator, and expands the opportunities to improve drug design, antibiotic development, and therapeutic approaches against pathogenic bacteria, especially for wound care.