Erdosteine Enhances Tobramycin Activity Against a Tobramycin-Resistant Clinical Isolate and PAO1 Reference Strain of Pseudomonas aeruginosa

Background Chronic respiratory infections caused by pathogens including Pseudomonas aeruginosa ( P. aeruginosa ) pose a major therapeutic challenge in patients with pulmonary diseases such as cystic fibrosis (CF) and non-CF bronchiectasis, where treatment efficacy is limited by the formation of biofilms, the emergence of multidrug resistant pathogens and a shortage of new and effective antibiotic classes. One approach to address this problem involves the use of “antibiotic enhancers”, which are compounds that potentiate the activity of existing antibiotics without possessing direct antimicrobial effects of their own. The mucoactive thiol-based prodrug erdosteine, currently approved for the treatment of acute and chronic respiratory diseases, has been reported to exhibit anti-adhesive activity against respiratory pathogens, suggesting a clinically relevant contribution to the prevention of bacterial colonisation. Furthermore, in addition to reported anti-inflammatory and antioxidant activities, erdosteine has demonstrated the ability to potentiate the activity of various antimicrobial drugs. However, to date, whether erdosteine can enhance the activity of tobramycin, an antibiotic widely used to treat pathogens in the respiratory tract, has not been investigated. In this study, we investigated the ability of MET-1, the primary active metabolite of erdosteine, to enhance the activity of tobramycin against P. aeruginosa strains using a panel of both in vitro and in vivo assays. Methods The activity of both mono- and combination therapies was measured in planktonic P. aeruginosa (strains RP73 & PAO1) using in vitro microdilution assays including chequerboard analysis and time-kill assays, whilst activity against biofilms were analysed using microtiter plate assays with readouts including total biomass, metabolic activity, and bacterial enumeration. Combination therapy of 40 mg/kg tobramycin and 100 mg/kg erdosteine was also assessed in vivo using a murine model of chronic pulmonary infection induced by P. aeruginosa. Results 10 mg/L MET-1 significantly enhanced the antimicrobial activity of tobramycin in planktonic cultures of RP73 at 24 h and PAO1 at 4 h, leading to a greater than 2 log 10 reduction in bacterial numbers compared to tobramycin monotherapy, despite MET-1 demonstrating no intrinsic bactericidal activity. In mature biofilms, MET-1 substantially enhanced tobramycin activity, reducing the biomass-derived IC₅₀ by approximately 18-fold in RP73 and 13-fold in PAO1. Finally, combination therapy of 40 mg/kg tobramycin and 100 mg/kg erdosteine was associated with a lower pulmonary bacterial burden in a murine model of chronic pulmonary infection. Conclusions Our in vitro and in vivo studies highlight the ability of erdosteine to potentiate the activity of tobramycin suggesting that erdosteine has the potential to reduce the burden of long-term antimicrobial therapies in patients with chronic respiratory infections and thus improve clinical outcomes.