Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Office of Research Services, National Institutes of Health, Bethesda, Maryland, USA.
J Infect Dis. 2010 Jun 15;201(12):1822-30. doi: 10.1086/652807.
Members of the Burkholderia cepacia complex (Bcc) cause considerable morbidity and mortality in patients with chronic granulomatous disease and cystic fibrosis. Many Bcc strains are antibiotic resistant, which requires the exploration of novel antimicrobial approaches, including antisense technologies such as phosphorodiamidate morpholino oligomers (PMOs).
Peptide-conjugated PMOs (PPMOs) were developed to target acpP, which encodes an acyl carrier protein (AcpP) that is thought to be essential for growth. Their antimicrobial activities were tested against different strains of Bcc in vitro and in infection models.
PPMOs targeting acpP were bactericidal against clinical isolates of Bcc (>4 log reduction), whereas a PPMO with a scrambled base sequence (scrambled PPMO) had no effect on growth. Human neutrophils were infected with Burkholderia multivorans and treated with AcpP PPMO. AcpP PPMO augmented killing, compared with neutrophils alone and compared with neutrophils alone plus scrambled PPMO. Mice with chronic granulomatous disease that were infected with B. multivorans were treated with AcpP PPMO, scrambled PPMO, or water at 0, 3, and 6 h after infection. Compared with water-treated control mice, the AcpP PPMO-treated mice showed an approximately 80% reduction in the risk of dying by day 30 of the experiment and relatively little pathology.
AcpP PPMO is active against Bcc infections in vitro and in vivo.
洋葱伯克霍尔德菌复合群（Bcc）的成员会导致慢性肉芽肿病和囊性纤维化患者的发病率和死亡率显著增加。许多 Bcc 菌株具有抗药性，这就需要探索新的抗菌方法，包括反义技术，如磷酰胺二酯吗啉寡聚物（PMO）。
开发了肽偶联 PMO（PPMO）来靶向 acpP，该基因编码一种酰基载体蛋白（AcpP），被认为是生长所必需的。它们的抗菌活性在体外和感染模型中针对不同的 Bcc 菌株进行了测试。
针对 acpP 的 PPMO 对临床分离的 Bcc 具有杀菌作用（>4 对数减少），而具有乱序碱基序列的 PPMO（乱序 PPMO）对生长没有影响。人类中性粒细胞被 Burkholderia multivorans 感染，并使用 AcpP PPMO 进行治疗。与单独的中性粒细胞相比，与单独的中性粒细胞加乱序 PPMO 相比，AcpP PPMO 增强了杀伤作用。感染 B. multivorans 的慢性肉芽肿病小鼠在感染后 0、3 和 6 小时用 AcpP PPMO、乱序 PPMO 或水进行治疗。与用水处理的对照组小鼠相比，用 AcpP PPMO 治疗的小鼠在实验的第 30 天死亡风险降低了约 80%，并且病理变化相对较小。
AcpP PPMO 对 Bcc 感染具有体外和体内活性。
