洋葱伯克霍尔德菌复合体
伯克氏菌属
微生物学
抗生素
生物
铜绿假单胞菌
囊性纤维化
痰
细菌
医学
肺结核
遗传学
病理
作者
Seth M. Daly,Carolyn R. Sturge,Kimberly R. Marshall-Batty,Christina F. Felder-Scott,Raksha Jain,Bruce L. Geller,David Greenberg
出处
期刊:ACS Infectious Diseases
[American Chemical Society]
日期:2018-02-20
卷期号:4 (5): 806-814
被引量:14
标识
DOI:10.1021/acsinfecdis.7b00235
摘要
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.
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