Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.
Pulmobiotics Ltd, Barcelona, Spain.
Nat Biotechnol. 2023 Aug;41(8):1089-1098. doi: 10.1038/s41587-022-01584-9. Epub 2023 Jan 19.
Engineered live bacteria could provide a new modality for treating lung infections, a major cause of mortality worldwide. In the present study, we engineered a genome-reduced human lung bacterium, Mycoplasma pneumoniae, to treat ventilator-associated pneumonia, a disease with high hospital mortality when associated with Pseudomonas aeruginosa biofilms. After validating the biosafety of an attenuated M. pneumoniae chassis in mice, we introduced four transgenes into the chromosome by transposition to implement bactericidal and biofilm degradation activities. We show that this engineered strain has high efficacy against an acute P. aeruginosa lung infection in a mouse model. In addition, we demonstrated that the engineered strain could dissolve biofilms formed in endotracheal tubes of patients with ventilator-associated pneumonia and be combined with antibiotics targeting the peptidoglycan layer to increase efficacy against Gram-positive and Gram-negative bacteria. We expect our M. pneumoniae-engineered strain to be able to treat biofilm-associated infections in the respiratory tract.
工程化活细菌可为治疗肺部感染提供新方法，肺部感染是全球主要致死原因之一。在本研究中，我们对一种经过基因删减的人类肺部细菌——肺炎支原体进行了工程化改造，以治疗呼吸机相关性肺炎，这种疾病与铜绿假单胞菌生物膜相关时具有很高的医院死亡率。在验证了减毒肺炎支原体底盘在小鼠中的生物安全性后，我们通过转座将四个转基因引入染色体，以实现杀菌和生物膜降解活性。我们表明，该工程菌株在急性铜绿假单胞菌肺部感染的小鼠模型中具有很高的疗效。此外，我们还证明，该工程菌株可以溶解呼吸机相关性肺炎患者气管内管中形成的生物膜，并与针对肽聚糖层的抗生素联合使用，以提高对抗革兰氏阳性和革兰氏阴性细菌的疗效。我们期望我们的肺炎支原体工程菌株能够治疗呼吸道生物膜相关感染。
