Therapeutic Inhibition of Metalloproteases by Tetracyclines during Infection by Multi-Drug Resistant Pseudomonas

Abstract

IntroductionBoth host and microbial proteases contribute to the destruction of tissue during Pseudomonas aeruginosa pulmonary infections. We previously reported that beneficial therapeutic effects of metalloprotease inhibitors in Pseudomonas aeruginosa pulmonary infections are not only from targeting the host matrix metalloproteases, the intended target, but also from cross-inhibition of the secreted bacterial metalloprotease LasB. MethodsWe used computation modeling and biochemical assays to investigate whether doxycycline and other structurally-related antibiotics of the tetracycline family inhibit the Pseudomonas protease, LasB. Modeling infection in vitro with human neutrophils and in vivo with a murine model of pulmonary infection, we investigate the effect of on tetracyclines inhibit LasB activity, bacterial survival, and inflammation. ResultsTetracycline, doxycycline, minocycline, and sanocycline all inhibit proteolysis by Pseudomonas LasB. At sub-antimicrobial concentrations, this sensitizes the bacterium killing by neutrophils. During pulmonary infection, tetracyclines significantly reduce pathological inflammation in the lung. ConclusionsOur study shows that tetracycline-family antibiotics, known inhibitors of mammalian matrix metalloproteinases, also inhibit LasB and have beneficial anti-inflammatory activity during infections by extensively drug-resistant P. aeruginosa. By controlling pathological host inflammation, inhibiting bacterial virulence factors, and directly killing bacteria, tetracyclines can have tripartite therapeutic benefits.