Open AccessOptimization of Acetazolamide-Based Scaffold as Potent Inhibitors of Vancomycin-Resistant Enterococcus
Author(s) -
Jatinder Kaur,
Xufeng Cao,
Nader S. Abutaleb,
Ahmed Elkashif,
Amanda Graboski,
Aaron D. Krabill,
Ahmed AbdelKhalek,
Weiwei An,
A. Bhardwaj,
Mohamed N. Seleem,
Daniel P. Flaherty
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c00734
Subject(s) - acetazolamide , carbonic anhydrase , chemistry , bioavailability , pharmacology , drug , enterococcus faecium , carbonic anhydrase inhibitor , drug resistance , microbiology and biotechnology , antibiotics , medicine , biochemistry , enzyme , biology
Vancomycin-resistant enterococci (VRE) are the second leading cause of hospital-acquired infections (HAIs) attributed to a drug-resistant bacterium in the United States, and resistance to the frontline treatments is well documented. To combat VRE, we have repurposed the FDA-approved carbonic anhydrase drug acetazolamide to design potent antienterococcal agents. Through structure-activity relationship optimization we have arrived at two leads possessing improved potency against clinical VRE strains from MIC = 2 μg/mL (acetazolamide) to MIC = 0.007 μg/mL ( 22 ) and 1 μg/mL ( 26 ). Physicochemical properties were modified to design leads that have either high oral bioavailability to treat systemic infections or low intestinal permeability to treat VRE infections in the gastrointestinal tract. Our data suggest the intracellular targets for the molecules are putative α-carbonic and γ-carbonic anhydrases, and homology modeling and molecular dynamics simulations were performed. Together, this study presents potential anti-VRE therapeutic options to provide alternatives for problematic VRE infections.