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Size matters – and how you measure it: a gram-negative antibacterial example exceeding typical molecular weight limits

Ruggiu, Fiorella and Yang, Shengtian and Robert, Simmons and Anthony, Casarez and Adriana, Jones and Cindy, Li and Jansen, Hanneke and Moser, Heinz and Charles, Dean and Folkert, Reck and Lindvall, Mika (2019) Size matters – and how you measure it: a gram-negative antibacterial example exceeding typical molecular weight limits. ACS Infectious Diseases. ISSN 2373-82272373-8227

Abstract

From a porin permeation perspective, we characterized a monobactam antibiotic (compound 1) which has a higher molecular weight (MW) than the upper limit of 600 Da typically applied in designing such compounds, yet the compound is active against Gram-negative bacteria. Despite a MW of 692 Da, the compound is able to adopt a compact conformation based on 2D NMR data. The dimensions, projection area and dipole moment derived from this conformation are compatible with porin permeation, as are locations of polar groups upon superimposition to the crystal structure of a known antibiotic, ampicillin, bound to E. coli OmpF porin crystal structure. MIC shifts in a porin knockout strain are also consistent with compound 1 predominately permeating through porins. In conclusion, we describe a carefully characterized case of a molecule outside default design parameters where MW does not adequately characterize the 3D shape which is more directly related to permeability. Leveraging 3D design criteria would open up additional chemical space currently underutilized due to limitations perceived in 2D.

Item Type: Article
Date Deposited: 18 Sep 2019 00:45
Last Modified: 18 Sep 2019 00:45
URI: https://oak.novartis.com/id/eprint/40169

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