Elimination of pulmonary Pseudomonas aeruginosa (PA) infections is challenging to accomplish with antibiotic therapies, mainly due to resistance mechanisms. Quorum sensing inhibitors (QSIs) interfering with biofilm formation can thus complement antibiotics. For simultaneous and improved delivery of both active agents to the infection sites, self‐assembling nanoparticles of a newly synthesized squalenyl hydrogen sulfate (SqNPs) were prepared. These nanocarriers allowed for remarkably high loading capacities of hydrophilic antibiotic tobramycin (Tob) and a novel lipophilic QSI at 30 % and circa 10 %, respectively. The drug‐loaded SqNPs showed improved biofilm penetration and enhanced efficacy in relevant biological barriers (mucin/human tracheal mucus, biofilm), leading to complete eradication of PA biofilms at circa 16‐fold lower Tob concentration than Tob alone. This study offers a viable therapy optimization and invigorates the research and development of QSIs for clinical use.
In light of the global
antimicrobial-resistance crisis, there is
an urgent need for novel bacterial targets and antibiotics with novel
modes of action. It has been shown that
Pseudomonas aeruginosa
elastase (LasB) and
Clostridium histolyticum
(
Hathewaya histolytica
) collagenase (ColH) play a significant
role in the infection process and thereby represent promising antivirulence
targets. Here, we report novel
N
-aryl-3-mercaptosuccinimide
inhibitors that target both LasB and ColH, displaying potent activities
in vitro
and high selectivity for the bacterial over human
metalloproteases. Additionally, the inhibitors demonstrate no signs
of cytotoxicity against selected human cell lines and in a zebrafish
embryo toxicity model. Furthermore, the most active ColH inhibitor
shows a significant reduction of collagen degradation in an
ex vivo
pig-skin model.
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