Therapeutic Inhibition of Metalloproteases by Tetracyclines During Infection by Multidrug-Resistant Pseudomonas

The secreted bacterial metalloprotease LasB contributes to inflammation and tissue damage during Pseudomonas aeruginosa pulmonary infections. We investigate whether tetracyclines inhibit LasB by computational modeling and biochemical assays, then examined their efficacy in model infections with human neutrophils in vitro and in a murine pulmonary model. Tetracycline, doxycycline, minocycline, and tigecycline all inhibited LasB proteolysis, while other relevant antibiotics did not. At subantimicrobial concentrations, tetracyclines sensitized Pseudomonas to neutrophil killing and significantly reduced lung pathology, even for multidrug-resistant strains. By controlling pathological host responses, inhibiting bacterial virulence factors, and facilitating bacterial killing, tetracyclines can thus have tripartite therapeutic benefits.