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Antisense Inhibitors Retain Activity in Pulmonary Models of Burkholderia Infection
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-02-20 00:00:00 , DOI: 10.1021/acsinfecdis.7b00235 Seth M. Daly 1 , Carolyn R. Sturge 1 , Kimberly R. Marshall-Batty 1 , Christina F. Felder-Scott 1 , Raksha Jain 1, 2 , Bruce L. Geller 3 , David E. Greenberg 1, 2
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-02-20 00:00:00 , DOI: 10.1021/acsinfecdis.7b00235 Seth M. Daly 1 , Carolyn R. Sturge 1 , Kimberly R. Marshall-Batty 1 , Christina F. Felder-Scott 1 , Raksha Jain 1, 2 , Bruce L. Geller 3 , David E. Greenberg 1, 2
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The Burkholderia cepacia complex is a group of Gram-negative bacteria that are opportunistic pathogens in immunocompromised individuals, such as those with cystic fibrosis (CF) or chronic granulomatous disease (CGD). Burkholderia are intrinsically resistant to many antibiotics and the lack of antibiotic development necessitates novel therapeutics. Peptide-conjugated phosphorodiamidate morpholino oligomers are antisense molecules that inhibit bacterial mRNA translation. Targeting of PPMOs to the gene acpP, which is essential for membrane synthesis, lead to defects in the membrane and ultimately bactericidal activity. Exploration of additional PPMO sequences identified the ATG and Shine-Dalgarno sites as the most efficacious for targeting acpP. The CF lung is a complex microenvironment, but PPMO inhibition was still efficacious in an artificial model of CF sputum. PPMOs had low toxicity in human CF cells at doses that were antibacterial. PPMOs also reduced the bacterial burden in the lungs of immunocompromised CyBB mice, a model of CGD. Finally, the use of multiple PPMOs was efficacious in inhibiting the growth of both Burkholderia and Pseudomonas in an in vitro model of coinfection. Due to the intrinsic resistance of Burkholderia to traditional antibiotics, PPMOs represent a novel and viable approach to the treatment of Burkholderia infections.
中文翻译：
反义抑制剂在伯克霍尔德氏菌感染的肺部模型中保留活性。
的洋葱伯克霍尔德氏菌复合物是一组革兰氏阴性菌是在免疫受损的个体条件致病菌，例如那些患有囊性纤维化（CF）或慢性肉芽肿病（CGD）的。伯克霍尔德氏菌本质上对许多抗生素具有抗性，而缺乏抗生素开发则需要新颖的治疗方法。肽缀合的二氨基氨基磷酸二氢吗啉代寡聚物是抑制细菌mRNA翻译的反义分子。靶向PPMOs的基因的ACPP，这对膜合成必不可少的，导致膜缺陷和最终的杀菌活性。通过探索其他PPMO序列，可以确定ATG和Shine-Dalgarno位点最有效地靶向acpP。CF肺是一个复杂的微环境，但是在CF痰的人工模型中PPMO抑制仍然有效。PPMO以抗菌剂量对人CF细胞具有低毒性。PPMO还可以降低免疫受损的CyBB小鼠（一种CGD模型）的肺部细菌负担。最后，在体外共感染模型中，多种PPMO的使用可有效抑制伯克霍尔德氏菌和假单胞菌的生长。由于伯克霍尔德氏菌对传统抗生素具有内在抗性，因此PPMOs是治疗伯克霍尔德氏菌感染的一种新颖可行的方法。
更新日期：2018-02-20
中文翻译：
反义抑制剂在伯克霍尔德氏菌感染的肺部模型中保留活性。
的洋葱伯克霍尔德氏菌复合物是一组革兰氏阴性菌是在免疫受损的个体条件致病菌，例如那些患有囊性纤维化（CF）或慢性肉芽肿病（CGD）的。伯克霍尔德氏菌本质上对许多抗生素具有抗性，而缺乏抗生素开发则需要新颖的治疗方法。肽缀合的二氨基氨基磷酸二氢吗啉代寡聚物是抑制细菌mRNA翻译的反义分子。靶向PPMOs的基因的ACPP，这对膜合成必不可少的，导致膜缺陷和最终的杀菌活性。通过探索其他PPMO序列，可以确定ATG和Shine-Dalgarno位点最有效地靶向acpP。CF肺是一个复杂的微环境，但是在CF痰的人工模型中PPMO抑制仍然有效。PPMO以抗菌剂量对人CF细胞具有低毒性。PPMO还可以降低免疫受损的CyBB小鼠（一种CGD模型）的肺部细菌负担。最后，在体外共感染模型中，多种PPMO的使用可有效抑制伯克霍尔德氏菌和假单胞菌的生长。由于伯克霍尔德氏菌对传统抗生素具有内在抗性，因此PPMOs是治疗伯克霍尔德氏菌感染的一种新颖可行的方法。
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