Membrane-Targeting DCAP Analogues with Broad-Spectrum Antibiotic Activity against Pathogenic Bacteria.
We performed a structure-activity relationship study of 2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2-(hydroxymethyl)propane-1,3-diol (DCAP), which is an antibacterial agent that disrupts the membrane potential and permeability of bacteria. The stereochemistry of DCAP had no effect on the biological activity of DCAP. The aromaticity and electronegativity of the chlorine-substituted carbazole was required for activity, suggesting that its planar and dipolar characteristics orient DCAP in membranes. Increasing the hydrophobicity of the tail region of DCAP enhanced its antibiotic activity. Two DCAP analogues displayed promising antibacterial activity against the BSL-3 pathogens Bacillus anthracis and Francisella tularensis. Codosing DCAP analogues with ampicillin or kanamycin increased their potency. These studies demonstrate that DCAP and its analogues may be a promising scaffold for developing chemotherapeutic agents that bind to bacterial membranes and kill strains of slow-growing or dormant bacteria that cause persistent infections.
Department of Biochemistry and Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
Katherine A
KA
Hurley
Department of Biochemistry and Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
Victoria A
VA
Heinrich
U.S. Army Medical Research Institute of Infectious Diseases , Fort Detrick, Maryland 21702, United States.
Jeremy R
JR
Hershfield
U.S. Army Medical Research Institute of Infectious Diseases , Fort Detrick, Maryland 21702, United States.
Samandra T
ST
Demons
Department of Biochemistry and Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States ; Department of Biochemistry and Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
Douglas B
DB
Weibel
Antibiotic; antimicrobial; bacterial membrane; broad-spectrum activity; chemotherapeutic