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ACS Infect Dis. 2018 Jun 8;4(6):988-997. doi: 10.1021/acsinfecdis.8b00010. Epub 2018 Mar 6.

Binding Mode Characterization and Early in Vivo Evaluation of Fragment-Like Thiols as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa.

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Department of Drug Design and Optimization , Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus E8.1 , 66123 , Saarbrücken , Germany.
Workgroup Structural Biology of Biosynthetic Enzymes , Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus E8.1 , 66123 , Saarbrücken , Germany.
Institute of Pharmaceutical Chemistry , Goethe University Frankfurt , Max-von-Laue-Straße 9 , 60438 , Frankfurt , Germany.
Department of Pharmacy, Pharmaceutical and Medicinal Chemistry , Saarland University , Campus E8.1 , 66123 , Saarbrücken , Germany.


The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported to inhibit LasB as well as collagenases from clostridia and bacillus species. The present work provides an insight into the structure-activity relationship (SAR) of these fragment-like LasB inhibitors, demonstrating an inverse activity profile compared to similar inhibitors of clostridial collagenase H (ColH). An X-ray cocrystal structure is presented, revealing distinct binding of two compounds to the active site of LasB, which unexpectedly maintains an open conformation. We further demonstrate in vivo efficacy in a Galleria mellonella infection model and high selectivity of the LasB inhibitors toward human matrix metalloproteinases (MMPs).


Galleria mellonella; LasB; antibiotic resistance; antivirulence agent; binding mode; elastase; selectivity

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