Pseudomonas aeruginosa is known as an opportunistic pathogen that often causes persistent infections associated with high level of antibiotic-resistance and biofilms formation. Chemical interference with bacterial cell-to-cell communication, termed quorum sensing (QS), has been recognized as an attractive approach to control infections and address the drug resistance problems currently observed worldwide. Instead of imposing direct selective pressure on bacterial growth, the right bioactive compounds can preferentially block QS-based communication and attenuate cascades of bacterial gene expression and production of virulence factors, thus leading to reduced pathogenicity. Herein, we report on the potential of itaconimides as quorum sensing inhibitors (QSI) of P. aeruginosa. An initial hit was discovered in a screening program of an in-house compound collection, and subsequent structure-activity relationship (SAR) studies provided analogs that could reduce expression of central QS-regulated virulence factors (elastase, rhamnolipid, and pyocyanin), and also successfully lead to the eradication of P. aeruginosa biofilms in combination with tobramycin. Further studies on the cytotoxicity of compounds using murine macrophages indicated no toxicity at common working concentrations, thereby pointing to the potential of these small molecules as promising entities for antimicrobial drug development.

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A convergent total synthesis of the natural mycobacterial iron chelator desferri-exochelin 772SM (D-EXO) is described. The synthetic procedure proceeds in 11 steps in the longest linear sequence, with an overall yield of 8.6%. The described procedure uses cheap starting materials and requires a limited number of chromatographic purifications. The concise strategy divides the exochelin into five key building blocks, allowing easy alternation of each single building block. Herein, the presented synthetic strategy is well suited to facilitate the synthesis of analogues and medicinal chemistry development efforts in a time- and resource-efficient manner.

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