Journal
ACS INFECTIOUS DISEASES
Volume 4, Issue 6, Pages 988-997Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.8b00010
Keywords
antibiotic resistance; antivirulence agent; elastase; LasB; binding mode; selectivity; Galleria mellonella
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Funding
- German Research Foundation (DFG) [PR1405/4-1]
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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 MMPs 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 (CoIH). 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).
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