Synthesis and Structure–Activity Studies of β-Barrel Assembly Machine Complex Inhibitor MRL-494

• DOI: 10.1021/acsinfecdis.2c00459
• Publication Date: 2022-11-01T19:59:43Z
• Authors: Nicola Wade; Charlotte M. J. W...; Paolo Innocenti; Cornelis J. Sling...; Gregory M. Koning...; Joen Luirink; Nathaniel I. Martin
• Keywords: Gram-Negative Bacteria; Structure–activity relationship; Guanidine

In the hunt for new antibiotics with activity against Gram-negative pathogens, outer membrane β-barrel assembly machine (BAM) complex has become an increasingly interesting target. The recently reported BAM inhibitor, MRL-494, was discovered via a screening campaign molecules that target membrane. Notably, MRL-494 to be unintended byproduct generated during synthesis of unrelated compound, and as such no compound disclosed. We here present convenient reliable route scales well. antibacterial measured synthesized matches in literature. Furthermore, found exhibit potent synergistic rifampicin bacteria, including E. coli, K. pneumoniae, A. baumannii, P. aeruginosa. also cause disruption induction Rcs stress response pathway. addition, we undertook focused structure–activity study specifically aimed at elucidating roles played by two guanidine moieties contained within structure MRL-494.