PDF(Pubmed)
Abstract：
The Burkholderia cepacia complex (Bcc) consists of opportunistic pathogens known to cause pneumonia in immunocompromised individuals, especially those with cystic fibrosis. Treating Bcc pneumonia is challenging due to the pathogens\' high multidrug resistance. Therefore, inhalation therapy with tobramycin powder, which can achieve high antibiotic concentrations in the lungs, is a promising treatment option. In this study, we investigated potential mechanisms that could compromise the effectiveness of tobramycin therapy. By selecting for B. cenocepacia survivors against tobramycin, we identified three spontaneous mutations that disrupt a gene encoding a key enzyme in the biosynthesis of cobalamin (Vitamin B12). This disruption may affect the production of succinyl-CoA by methylmalonyl-CoA mutase, which requires adenosylcobalamin as a cofactor. The depletion of cellular succinyl-CoA may impact the tricarboxylic acid (TCA) cycle, which becomes metabolically overloaded upon exposure to tobramycin. Consequently, the mutants exhibited significantly reduced reactive oxygen species (ROS) production. Both the wild-type and mutants showed tolerance to tobramycin and various other bactericidal antibiotics under microaerobic conditions. This suggests that compromised ROS-mediated killing, due to the impacted TCA cycle, underlies the mutants\' tolerance to bactericidal antibiotics. The importance of ROS-mediated killing and the potential emergence of mutants that evade it through the depletion of cobalamin (Vitamin B12) provide valuable insights for developing strategies to enhance antibiotic treatments of Bcc pneumonia.
摘要：
洋葱伯克霍尔德氏菌（Bcc）由已知在免疫功能低下的个体中引起肺炎的机会病原体组成。尤其是那些囊性纤维化患者.由于病原体的高多药耐药性，治疗Bcc肺炎具有挑战性。因此,妥布霉素粉吸入疗法，可以在肺部达到高浓度的抗生素，是一个很有前途的治疗选择。在这项研究中,我们研究了可能影响妥布霉素治疗有效性的潜在机制.通过选择针对妥布霉素的伯克霍尔德氏菌幸存者，我们发现了3个自发突变,它们破坏了编码钴胺素(维生素B12)生物合成关键酶的基因.这种破坏可能会影响甲基丙二酰辅酶A变位酶产生琥珀酰辅酶A，这需要腺苷钴胺作为辅因子。细胞琥珀酰辅酶A的消耗可能会影响三羧酸（TCA）循环，暴露于妥布霉素后代谢过载。因此,突变体显示出显着降低的活性氧（ROS）的产生。在微氧条件下，野生型和突变体均对妥布霉素和各种其他杀菌抗生素具有耐受性。这表明ROS介导的杀伤功能受损，由于受影响的TCA循环，突变体对杀菌抗生素的耐受性。ROS介导的杀死的重要性和通过消耗钴胺素（维生素B12）逃避它的突变体的潜在出现为开发策略以增强Bcc肺炎的抗生素治疗提供了有价值的见解。
