ABSTRACT
Tetracyclines (TCs) are an important class of antibiotics threatened by an emerging new resistance mechanismâenzymatic inactivation. These TC-inactivating enzymes, also known as tetracycline destructases (TDases), inactivate all known TC antibiotics, including drugs of last resort. Combination therapies consisting of a TDase inhibitor and a TC antibiotic represent an attractive strategy for overcoming this type of antibiotic resistance. Here, we report the structure-based design, synthesis, and evaluation of bifunctional TDase inhibitors derived from anhydrotetracycline (aTC). By appending a nicotinamide isostere to the C9 position of the aTC D-ring, we generated bisubstrate TDase inhibitors. The bisubstrate inhibitors have extended interactions with TDases by spanning both the TC and presumed NADPH binding pockets. This simultaneously blocks TC binding and the reduction of FAD by NADPH while "locking" TDases in an unproductive FAD "out" conformation.
Subject(s)
Heterocyclic Compounds , Tetracycline , Tetracycline/pharmacology , Tetracycline/metabolism , NADP/metabolism , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Tetracyclines/pharmacology , Protein Synthesis Inhibitors , Oxidation-ReductionABSTRACT
Traumatic brain injury (TBI) is a common and prevalent condition that affects large numbers of people across a range of ages. Individuals engaging in physical activities and victims of accidents are at a higher risk for TBI. There is a lack of available treatment specifically for TBI. Given the difficulty to determine its precise location in the brain, TBI remains difficult to fully diagnose or treat. Herein, we disclose a novel strategy for directing therapeutic agents to TBI sites, without the need to determine the precise location of the TBI activity in the brain. This novel approach is based on the use of a cyanine dye nanocage carrying Gabapentin, a known TBI therapeutic agent. Upon exposure of the cyanine nanocage to near-infrared light, the local release of Gabapentin is triggered, selectively at the TBI-affected site.