Size Matters and How You Measure It: A Gram-Negative Antibacterial Example Exceeding Typical Molecular Weight Limits.
ACS Infect Dis
; 5(10): 1688-1692, 2019 10 11.
Article
en En
| MEDLINE
| ID: mdl-31478369
ABSTRACT
Monobactam antibiotic 1 is active against Gram-negative bacteria even though it has a higher molecular weight (MW) than the limit of 600 Da typically applied in designing such compounds. On the basis of 2D NMR data, the compound is able to adopt a compact conformation. 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 ampicillin bound to E. coli OmpF porin. Minimum inhibitory concentration (MIC) shifts in a porin knock-out strain are also consistent with 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 represent the 3D shape more directly related to permeability. Leveraging 3D design criteria would open up additional chemical space currently underutilized due to limitations perceived in 2D.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
3_ND
Problema de salud:
3_neglected_diseases
/
3_zoonosis
Asunto principal:
Monobactamas
/
Bacterias Gramnegativas
/
Antibacterianos
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
ACS Infect Dis
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos