title: Antibacterial Characterization of Novel Synthetic Thiazole Compounds against Methicillin-Resistant Staphylococcus pseudintermedius.
abstract: Staphylococcus pseudintermedius is a commensal organism of companion animals that is a significant source of opportunistic infections in dogs. With the emergence of clinical isolates of S. pseudintermedius (chiefly methicillin-resistant S. pseudintermedius (MRSP)) exhibiting increased resistance to nearly all antibiotic classes, new antimicrobials and therapeutic strategies are urgently needed. Thiazole compounds have been previously shown to possess potent antibacterial activity against multidrug-resistant strains of Staphylococcus aureus of human and animal concern. Given the genetic similarity between S. aureus and S. pseudintermedius, this study explores the potential use of thiazole compounds as novel antibacterial agents against methicillin-sensitive S. pseudintermedius (MSSP) and MRSP. A broth microdilution assay confirmed these compounds exhibit potent bactericidal activity (at sub-microgram/mL concentrations) against both MSSA and MRSP clinical isolates while the MTS assay confirmed three compounds (at 10 μg/mL) were not toxic to mammalian cells. A time-kill assay revealed two derivatives rapidly kill MRSP within two hours. However, this rapid bactericidal activity was not due to disruption of the bacterial cell membrane indicating an alternative mechanism of action for these compounds against MRSP. A multi-step resistance selection analysis revealed compounds 4 and 5 exhibited a modest (two-fold) shift in activity over ten passages. Furthermore, all six compounds (at a subinihibitory concentration) demonstrated the ability to re-sensitize MRSP to oxacillin, indicating these compounds have potential use for extending the therapeutic utility of β-lactam antibiotics against MRSP. Metabolic stability analysis with dog liver microsomes revealed compound 3 exhibited an improved physicochemical profile compared to the lead compound. In addition to this, all six thiazole compounds possessed a long post-antibiotic effect (at least 8 hours) against MRSP. Collectively the present study demonstrates these synthetic thiazole compounds possess potent antibacterial activity against both MSSP and MRSP and warrant further investigation into their use as novel antimicrobial agents.
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, Indiana, United States of America.
authors.forename: Haroon
authors.initials: H
authors.lastname: Mohammad
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy West Lafayette, Indiana, United States of America; Purdue Center for Cancer Research, West Lafayette, Indiana, United States of America.
authors.forename: P V Narasimha
authors.initials: PV
authors.lastname: Reddy
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy West Lafayette, Indiana, United States of America; Purdue Center for Cancer Research, West Lafayette, Indiana, United States of America.
authors.forename: Dennis
authors.initials: D
authors.lastname: Monteleone
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy West Lafayette, Indiana, United States of America; Purdue Center for Cancer Research, West Lafayette, Indiana, United States of America.
authors.forename: Abdelrahman S
authors.initials: AS
authors.lastname: Mayhoub
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy West Lafayette, Indiana, United States of America; Purdue Center for Cancer Research, West Lafayette, Indiana, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, Indiana, United States of America.
authors.forename: G Kenitra
authors.initials: GK
authors.lastname: Hammac
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, Indiana, United States of America.
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Seleem
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004283:Dog Diseases / Q000188:drug therapy / Q000382:microbiology*; D004285:Dogs; D008248:Lysostaphin / Q000494:pharmacology; D008712:Methicillin / Q000494:pharmacology; D016106:Methicillin Resistance; D051379:Mice; D008826:Microbial Sensitivity Tests; D010068:Oxacillin / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology / Q000662:veterinary*; D013210:Staphylococcus / Q000187:drug effects* / Q000302:isolation & purification; D013844:Thiazoles / Q000494:pharmacology* / Q000633:toxicity; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D013844:Thiazoles; D014640:Vancomycin; D008248:Lysostaphin; D008712:Methicillin; D010068:Oxacillin; D012293:Rifampin