Engineered live bacteria could provide a new modality for treating lung infections, a major cause of mortality worldwide. This study engineered a genome-reduced human lung bacterium, *Mycoplasma pneumoniae*, to treat ventilator-associated pneumonia (VAP), particularly when associated with *Pseudomonas aeruginosa* biofilms. After validating the biosafety of an attenuated *M. pneumoniae* strain in mice, four transgenes were introduced to enhance bactericidal and biofilm degradation activities. The engineered strain showed high efficacy against acute *P. aeruginosa* lung infection in a mouse model, dissolved biofilms in endotracheal tubes from VAP patients, and synergistically increased antibiotic efficacy against Gram-positive and Gram-negative bacteria. This engineered *M. pneumoniae* strain holds promise for treating biofilm-associated respiratory tract infections.

Rocco Mazzolini, Irene Rodríguez-Arce, Laia Fernández-Barat, Carlos Piñero-Lambea, Victoria Garrido, Agustín Rebollada-Merino, Anna Motos, Antoni Torres, Maria Jesús Grilló, Luis Serrano, Maria Lluch-Senar