<i>Pseudomonas aeruginosa</i> is of major concern for cystic fibrosis patients where this infection can be fatal. With the emergence of drug-resistant strains, there is an urgent need to develop novel antibiotics against <i>P. aeruginosa</i>. MurB is a promising target for novel antibiotic development as it is involved in the cell wall biosynthesis. MurB has been shown to be essential in <i>P. aeruginosa</i>, and importantly, no MurB homologue exists in eukaryotic cells. A fragment-based drug discovery approach was used to target <i>Pa</i> MurB. This led to the identification of a number of fragments, which were shown to bind to MurB. One fragment, a phenylpyrazole scaffold, was shown by ITC to bind with an affinity of <i>K</i><sub>d</sub> = 2.88 mM (LE 0.23). Using a structure guided approach, different substitutions were synthesized and the initial fragment was optimized to obtain a small molecule with <i>K</i><sub>d</sub> = 3.57 μM (LE 0.35).