Antibacterial Characterization of Novel Synthetic Thiazole Compounds against Methicillin-Resistant Staphylococcus pseudintermedius

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dc.contributor.authorMohammad, Haroonen
dc.contributor.authorReddy, PV Narasimha V. N.en
dc.contributor.authorMonteleone, Dennisen
dc.contributor.authorMayhoub, Abdelrahman S.en
dc.contributor.authorCushman, Marken
dc.contributor.authorHammac, G. Kenitraen
dc.contributor.authorSeleem, Mohamed N.en
dc.date.accessioned2020-09-21T16:18:10Zen
dc.date.available2020-09-21T16:18:10Zen
dc.date.issued2015-06-18en
dc.date.updated2020-09-21T16:18:08Zen
dc.description.abstractStaphylococcus 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 multistep resistance selection analysis revealed compounds 4 and 5 exhibited a modest (twofold) 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.en
dc.description.versionPublished versionen
dc.format.extent19 page(s)en
dc.format.mediumElectronic-eCollectionen
dc.format.mimetypeapplication/pdfen
dc.identifierARTN e0130385 (Article number)en
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0130385en
dc.identifier.eissn1932-6203en
dc.identifier.issn1932-6203en
dc.identifier.issue6en
dc.identifier.orcidSeleem, Mohamed [0000-0003-0939-0458]en
dc.identifier.otherPONE-D-15-05317 (PII)en
dc.identifier.pmid26086336 (pubmed)en
dc.identifier.urihttp://hdl.handle.net/10919/100046en
dc.identifier.volume10en
dc.language.isoenen
dc.publisherPLoSen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectCLINICAL-SAMPLESen
dc.subjectAUREUSen
dc.subjectPREVALENCEen
dc.subjectINFECTIONen
dc.subjectAGENTSen
dc.subjectDOGSen
dc.subjectANTIBIOTICSen
dc.subjectCOMBINATIONen
dc.subjectVANCOMYCINen
dc.subjectRIFAMPICINen
dc.subject.meshCell Lineen
dc.subject.meshAnimalsen
dc.subject.meshDogsen
dc.subject.meshMiceen
dc.subject.meshStaphylococcusen
dc.subject.meshStaphylococcal Infectionsen
dc.subject.meshDog Diseasesen
dc.subject.meshMethicillinen
dc.subject.meshOxacillinen
dc.subject.meshThiazolesen
dc.subject.meshRifampinen
dc.subject.meshLysostaphinen
dc.subject.meshVancomycinen
dc.subject.meshAnti-Bacterial Agentsen
dc.subject.meshMicrobial Sensitivity Testsen
dc.subject.meshMethicillin Resistanceen
dc.subject.meshCell Survivalen
dc.titleAntibacterial Characterization of Novel Synthetic Thiazole Compounds against Methicillin-Resistant Staphylococcus pseudintermediusen
dc.title.serialPLoS Oneen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2015-05-20en
pubs.organisational-group/Virginia Tech/Veterinary Medicineen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/CVM T&R Facultyen
pubs.organisational-group/Virginia Techen

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