Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram-negative pathogen Pseudomonas aeruginosa secretes the virulence factor elastase B (LasB), which plays an important role in the infection process. Here, we report a submicromolar, non-peptidic, fragment-like inhibitor of LasB discovered by careful visual inspection of structural data. Inspired by the natural LasB substrate, the original fragment was successfully merged and grown. The optimized inhibitor is accessible via simple chemistry and retained selectivity with a substantial improvement in activity, which can be rationalized by the crystal structure of LasB in complex with the inhibitor. We also demonstrate an improved in vivo efficacy of the optimized hit in Galleria mellonella larvae, highlighting the significance of this class of compounds as promising drug candidates.Alternative binding modes are often observed in the realm of fragment-based drug design. [1] Despite the potential to significantly accelerate hit-to-lead optimization, there are few examples of successful fragment linking/merging or systematic exploitation of such invaluable sources of structural information. This is presumably due to a number of conditions that need to be met such as the linker composition and the resulting ADMET properties. [2,3] We [

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