title: In Vitro Antibacterial Activity of Rhodanine Derivatives against Pathogenic Clinical Isolates.
abstract: Bacterial infections present a serious challenge to healthcare practitioners due to the emergence of resistance to numerous conventional antibacterial drugs. Therefore, new bacterial targets and new antimicrobials are unmet medical needs. Rhodanine derivatives have been shown to possess potent antimicrobial activity via a novel mechanism. However, their potential use as antibacterials has not been fully examined. In this study, we determined the spectrum of activity of seven rhodanine derivatives (compounds Rh 1-7) against clinical isolates of Gram-positive and Gram-negative bacterial strains and Candida albicans. We also synthesized and tested three additional compounds, ethyl ester and amide of rhodanine 2 (Rh 8 and Rh 10, respectively) and ethyl ester of rhodanine 3 (Rh 9) to determine the significance of the carboxyl group modification towards antibacterial activity and human serum albumin binding. A broth microdilution assay confirmed Rh 1-7 exhibit bactericidal activity against Gram-positive pathogens. Rh 2 had significant activity against various vancomycin-resistant (MIC90 = 4 μM) and methicillin-resistant (MIC90 = 4 μM) Staphylococcus aureus (VRSA and MRSA), Staphylococcus epidermidis (MIC = 4 μM) and vancomycin-resistant Enterococcus (VRE) strains (MIC90 = 8 μM). The rhodanine compounds exhibited potent activity against Bacillus spp., including Bacillus anthracis, with MIC range of 2-8 μM. In addition, they had potent activity against Clostridium difficile. The most potent compound, Rh 2, at 4 and 8 times its MIC, significantly decreased S. epidermidis biofilm mass by more than 35% and 45%, respectively. None of the rhodanine compounds showed antimicrobial activity (MIC > 128 μM) against various 1) Gram-negative pathogens (Acinetobacter baumannii, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, and Salmonella Typhimurium) or 2) strains of Candida albicans (MIC > 64 μM). The MTS assay confirmed that rhodanines were not toxic to mouse murine macrophage (J774.1A) up to 64 μM, human keratinocytes (HaCat) up to 32 μM, and human ileocecal colorectal cell (HRT-18) up to 128 μM. Overall, these data suggest that certain rhodanine compounds may have potential use for the treatment of several multidrug-resistant Gram-positive bacterial infections.
authors.affiliation: Department of Comparative Pathology, College of Veterinary Medicine, Purdue University, 625 Harrison Street, West Lafayette, Indiana, 47907, United States of America.
authors.forename: Ahmed
authors.initials: A
authors.lastname: AbdelKhalek
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York, 11439, United States of America.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York, 11439, United States of America.
authors.forename: Bhargav A
authors.initials: BA
authors.lastname: Patel
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York, 11439, United States of America.
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
authors.affiliation: Department of Comparative Pathology, College of Veterinary Medicine, Purdue University, 625 Harrison Street, West Lafayette, Indiana, 47907, United States of America.|Purdue Institute for Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, Indiana, 47907, United States of America.
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Seleem
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001419:Bacteria / Q000166:cytology / Q000187:drug effects*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008826:Microbial Sensitivity Tests; D012236:Rhodanine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D012709:Serum Albumin / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D012709:Serum Albumin; D012236:Rhodanine