Vancomycin-resistant Enterococci (VRE) are the second leading cause of hospital-acquired infections. In the US, an estimated 20,000 patients become infected with it each year, and nearly 10% of people who get it die from it. Researchers from Purdue University published in the Journal of Medicinal Chemistry (https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.0c00734) that they have repurposed the FDA-approved carbonic anhydrase drug acetazolamide to design potent antienterococcal agents. Their data suggest the intracellular targets for the molecules are reputed α-carbonic and γ-carbonic anhydrases, and homology modeling and molecular dynamics simulations were performed. The potency of the molecules and the ability to target VRE in different compartments of the body is novel. The discovery may help to change the way people treat VRE in the future. The researchers have been able to improve the effectiveness of this drug 600 times better than where we started in treating VRE. Together, this study presents potential anti-VRE therapeutic options to provide alternatives for problematic VRE infections. The Purdue team’s small molecules have been shown to target VRE and have the properties necessary to treat VRE in both systemic circulations or in the GI tract, where all VRE infections originate. @ https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.0c00734