title: Optimization of a novel series of pyranopyridine RND efflux pump inhibitors.
abstract: The rise of multidrug resistant (MDR) Gram-negative pathogens complicates our ability to treat bacterial infections with antibiotics. MDR efflux pumps play a major role in the acquisition and expression of the MDR phenotype. The major MDR efflux pumps in Gram-negative pathogens are the resistance-nodulation-division (RND) superfamily pumps. Efflux pump inhibitors (EPIs) that target RND superfamily pumps could play an important role in the clinic as an adjunctive therapy to increase antibiotic efficacy, decrease resistance, and attenuate virulence in Gram-negative pathogens. Here, we review recent advances in the discovery and structurally enabled optimization of a novel series of RND-targeting pyranopyridine EPIs currently in the early stages of lead optimization.
authors.affiliation: Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, United States.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Aron
authors.affiliation: Microbiotix, Inc., One Innovation Dr., Worcester, MA 01605, United States. Electronic address: topperman@microbiotix.com.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Opperman
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D011714:Pyrans / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000596829:AcrAB-TolC protein, E coli; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D029968:Escherichia coli Proteins; C000591634:MBX2319; D026901:Membrane Transport Proteins; D011714:Pyrans; D011725:Pyridines