A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms

Abstract

Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) – a crucial transcriptional regulator serving major functions in PA virulence – can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry‐driven hit‐to‐lead optimization and in‐depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter‐gene with IC50 values as low as 200 and 11 × 10−9 m, respectively. Drug metabolism and pharmacokinetics (DMPK) as well as safety pharmacology studies especially highlight the promising translational properties of the lead QSI for pulmonary applications. Moreover, target engagement of the lead QSI is shown in a PA mucoid lung infection mouse model. Beyond that, a significant synergistic effect of a QSI‐tobramycin (Tob) combination against PA biofilms using a tailor‐made squalene‐derived nanoparticle (NP) formulation, which enhance the minimum biofilm eradicating concentration (MBEC) of Tob more than 32‐fold is demonstrated. The novel lead QSI and the accompanying NP formulation highlight the potential of adjunctive pathoblocker‐mediated therapy against PA infections opening up avenues for preclinical development.

Towards the sustainable discovery and development of new antibiotics

“…The chosen target product profile (TPP) is defined as a pathogen-specific inhaled adjunctive treatment of chronic respiratory PA infections in combination with a standard-of-care (SoC) backbone antibiotic. Resulting pre-candidates have nanomolar on-target and cellular efficacy, potentiate tobramycin efficacy against PA biofilms, show high exposures in vivo (various routes intratracheal, intravenous, subcutaneous, peroral) and no overt findings in safety pharmacology screens 333 . While demonstration of in vivo target engagement by means of signal molecule quantification was achieved swiftly in a mucoid acute murine lung infection model, assaying in vivo treatment efficacy related to the pathoblocker-specific activities remains a considerable challenge.…”

Structure-Guided Optimization of Small-Molecule Folate Uptake Inhibitors Targeting the Energy-Coupling Factor Transporters

“…The superb inhibition of 15 and 48 encouraged us to further evaluate their minimal inhibitory concentrations (MIC) against a broad panel of clinically relevant Gram-positive pathogens, alongside with their solubility and cytotoxic effects on human liver cancer cells (HepG2) (Table 5). Both 15 and 48 showed good kinetic solubility 26 indicating adequate access the envisaged P2 pocket of the transmembrane protein since further cell uptake is not necessary. Unfortunately, we observed only a slight antimicrobial effect of 15 and 48 for Staphylococcus aureus, suggesting that S. aureus not necessary relies on the folate uptake and predominantly obtains it directly via the biosynthesis.…”

Bacteria‐Targeting Photodynamic Nanoassemblies for Efficient Treatment of Multidrug‐Resistant Biofilm Infected Keratitis

“…Multiple virulence factors produced by P. aeruginosa are controlled by QS, which is involved in biofilm formation, and also associated with full pathogenicity. [42,43] PvdA is related with siderophore biosynthesis. [44] As a result, the generation of ROS caused DNA damage and proteins damage, meanwhile, decreasing the expression level of virulence factors, which may benefit the solving of MDR-P. aeruginosa biofilm.…”