| Institution: | 1. Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States;2. The University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology, 1703 E. Mabel St., PO Box 210207, Tucson, AZ 85721, United States;3. Stark Neurosciences Research Institute, Indiana University School of Medicine. 320 W. 15th Street, Suite 414, Indianapolis, IN 46202, United States;4. Department of Neurology, Indiana University School of Medicine. 635 Barnhill Drive, Indianapolis, IN 46202, United States;1. Synthia LLC, Davis, CA 95616, United States;2. Department of Entomology and Nematology, One Shields Ave, University of California-Davis, Davis, CA 95616, United States;3. EicOsis Human Health, 140 B Street, Suite 5, Number 346, Davis, CA 95616, United States;1. Universidade Federal de Pernambuco (UFPE), Departamento de Antibióticos (DANTI), 50670-901 Recife, PE, Brazil;2. Universidade Estadual da Paraíba (UEPB), Departamento de Farmácia, 58429-500 Campina Grande, PB, Brazil;3. Fundação Oswaldo Cruz, Centro de Pesquisa Gonçalo Moniz/Laboratório de Engenharia Tecidual e Imunofarmacologia, 40296-710 Salvador, BA, Brazil;4. Universidade de Pernambuco (UPE), Faculdade de Ciências, Educação e Tecnologia de Garanhuns (FACETEG), 55290-000 Garanhuns, PE, Brazil;5. Universidade Federal Rural de Pernambuco (UFRPE), Unidade Acadêmica de Serra Talhada (UAST), 56909-535 Serra Talhada, PE, Brazil;1. Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China;2. Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science and Technology Normal University, Fenglin Street, Nanchang, Jiangxi 330013, PR China;1. Biodiscovery Institute, School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom;2. Institute of Microbiology and Infection, School of Bioscience, University of Birmingham, Birmingham B15 2TT, United Kingdom |
| Abstract: | In two previous studies, we identified compound 1 as a moderate GroEL/ES inhibitor with weak to moderate antibacterial activity against Gram-positive and Gram-negative bacteria including Bacillus subtilis, methicillin-resistant Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, and SM101 Escherichia coli (which has a compromised lipopolysaccharide biosynthetic pathway making bacteria more permeable to drugs). Extending from those studies, we developed two series of analogs with key substructures resembling those of known antibacterials, nitroxoline (hydroxyquinoline moiety) and nifuroxazide/nitrofurantoin (bis-cyclic-N-acylhydrazone scaffolds). Through biochemical and cell-based assays, we identified potent GroEL/ES inhibitors that selectively blocked E. faecium, S. aureus, and E. coli proliferation with low cytotoxicity to human colon and intestine cells in vitro. Initially, only the hydroxyquinoline-bearing analogs were found to be potent inhibitors in our GroEL/ES-mediated substrate refolding assays; however, subsequent testing in the presence of an E. coli nitroreductase (NfsB) in situ indicated that metabolites of the nitrofuran-bearing analogs were potent GroEL/ES inhibitor pro-drugs. Consequently, this study has identified a new target of nitrofuran-containing drugs, and is the first reported instance of such a unique class of GroEL/ES chaperonin inhibitors. The intriguing results presented herein provide impetus for expanded studies to validate inhibitor mechanisms and optimize this antibacterial class using the respective GroEL/ES chaperonin systems and nitroreductases from E. coli and the ESKAPE bacteria. |
