Howard James J, Sturge Carolyn R, Moustafa Dina A, Daly Seth M, Marshall-Batty Kimberly R, Felder Christina F, Zamora Danniel, Yabe-Gill Marium, Labandeira-Rey Maria, Bailey Stacey M, Wong Michael, Goldberg Joanna B, Geller Bruce L, Greenberg David E
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Antimicrob Agents Chemother. 2017 Mar 24;61(4). doi: 10.1128/AAC.01938-16. Print 2017 Apr.
is a highly virulent, multidrug-resistant pathogen that causes significant morbidity and mortality in hospitalized patients and is particularly devastating in patients with cystic fibrosis. Increasing antibiotic resistance coupled with decreasing numbers of antibiotics in the developmental pipeline demands novel antibacterial approaches. Here, we tested peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), which inhibit translation of complementary mRNA from specific, essential genes in PPMOs targeted to , , and , inhibited growth in many clinical strains and activity of PPMOs could be enhanced 2- to 8-fold by the addition of polymyxin B nonapeptide at subinhibitory concentrations. The PPMO targeting was also effective at preventing PAO1 biofilm formation and at reducing existing biofilms. Importantly, treatment with various combinations of a PPMO and a traditional antibiotic demonstrated synergistic growth inhibition, the most effective of which was the PPMO targeting with tobramycin. Furthermore, treatment of PA103-infected mice with PPMOs targeting , , or significantly reduced the bacterial burden in the lungs at 24 h by almost 3 logs. Altogether, this study demonstrates that PPMOs targeting the essential genes , , or in are highly effective at inhibiting growth and These data suggest that PPMOs alone or in combination with antibiotics represent a novel approach to addressing the problems associated with rapidly increasing antibiotic resistance in .
是一种高毒力、多重耐药的病原体，可导致住院患者出现严重发病和死亡情况，对囊性纤维化患者尤其具有毁灭性。抗生素耐药性不断增加，加之处于研发阶段的抗生素数量不断减少，因此需要新的抗菌方法。在此，我们测试了肽缀合的磷酰二胺吗啉代寡聚物（PPMO），其可抑制来自特定必需基因的互补mRNA的翻译。针对、和的PPMO可抑制许多临床菌株中的生长，并且通过添加亚抑制浓度的多粘菌素B九肽，PPMO的活性可提高2至8倍。靶向的PPMO在预防PAO1生物膜形成和减少现有生物膜方面也有效。重要的是，用PPMO与传统抗生素的各种组合进行治疗显示出协同生长抑制作用，其中最有效的是靶向的PPMO与妥布霉素联用。此外，用靶向、或的PPMO治疗PA103感染的小鼠，在24小时时可使肺部细菌载量显著降低近3个对数。总之，本研究表明，靶向中的必需基因、或的PPMO在抑制生长方面非常有效。这些数据表明，单独使用PPMO或与抗生素联合使用代表了一种解决与中迅速增加的抗生素耐药性相关问题的新方法。
