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

• Published in: ACS infectious diseases Vol. 4; no. 6; pp. 988 - 997
• Main Authors: Kany, Andreas M., Sikandar, Asfandyar, Haupenthal, Jörg, Yahiaoui, Samir, Maurer, Christine K., Proschak, Ewgenij, Köhnke, Jesko, Hartmann, Rolf W.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08.06.2018
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Binding Sites; Cell Line; Chromatography, Liquid; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Humans; Mass Spectrometry; Metalloendopeptidases - antagonists & inhibitors; Metalloendopeptidases - chemistry; Models, Molecular; Molecular Conformation; Molecular Structure; Moths - microbiology; Protein Binding; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - pathogenicity; Pseudomonas aeruginosa - physiology; Structure-Activity Relationship; Sulfhydryl Compounds - chemical synthesis; Sulfhydryl Compounds - chemistry; Sulfhydryl Compounds - pharmacology; Virulence Factors; elastase; LasB; selectivity; antivirulence agent; binding mode; antibiotic resistance; Galleria mellonella
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.8b00010

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).