Synthesis and Structure–Activity Studies of β-Barrel Assembly Machine Complex Inhibitor MRL-494
ACS Infectious Diseases, vol. 8, pp. 2242–2252
Abstract
High Resolution Image Download MS PowerPoint Slide In the hunt for new antibiotics with activity against Gram-negative pathogens, the outer membrane β-barrel assembly machine (BAM) complex has become an increasingly interesting target. The recently reported BAM complex inhibitor, MRL-494, was discovered via a screening campaign for molecules that target the outer membrane. Notably, MRL-494 was reported to be an unintended byproduct generated during the synthesis of an unrelated compound, and as such no synthesis of the compound was disclosed. We here present a convenient and reliable route for the synthesis of MRL-494 that scales well. The antibacterial activity measured for synthesized MRL-494 matches that reported in the literature. Furthermore, MRL-494 was found to exhibit potent synergistic activity with rifampicin against Gram-negative bacteria, including E. coli, K. pneumoniae, A. baumannii, and P. aeruginosa . MRL-494 was also found to cause outer membrane disruption and induction of the Rcs stress response pathway. In addition, we undertook a focused structure–activity study specifically aimed at elucidating the roles played by the two guanidine moieties contained within the structure of MRL-494.
Authors 7
-
Affiliation as printed
Biological Chemistry Group, Institute of Biology Leiden, Leiden University, 2333 BE Leiden, The Netherlands
-
Affiliation as printed
Biological Chemistry Group, Institute of Biology Leiden, Leiden University, 2333 BE Leiden, The Netherlands
-
Affiliation as printed
Biological Chemistry Group, Institute of Biology Leiden, Leiden University, 2333 BE Leiden, The Netherlands
-
Affiliation as printed
Biological Chemistry Group, Institute of Biology Leiden, Leiden University, 2333 BE Leiden, The Netherlands
-
Affiliation as printed
Department of Molecular Microbiology, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit, 1081 HV Amsterdam, The Netherlands
-
Affiliation as printed
Department of Molecular Microbiology, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit, 1081 HV Amsterdam, The Netherlands
-
Affiliation as printed
Biological Chemistry Group, Institute of Biology Leiden, Leiden University, 2333 BE Leiden, The Netherlands
Cited by 13 stored of 13
13 results
No patents citing this paper on Lens.org (checked 2026-10-11).