Antimicrobial activity of a natural compound and analogs against multi-drug-resistant Gram-positive pathogens

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dc.citation.articleNumbere01515-22
dc.citation.issueNumber3
dc.citation.journalTitleMicrobiology Spectrum
dc.citation.volumeNumber12
dc.contributor.authorShah, Kush N.
dc.contributor.authorShah, Parth N.
dc.contributor.authorAgobe, Francesca O.
dc.contributor.authorLovato, Kaitlyn
dc.contributor.authorGao, Hongyin
dc.contributor.authorOgun, Oluwadara
dc.contributor.authorHoffman, Cason
dc.contributor.authorYabe-Gill, Marium
dc.contributor.authorChen, Qingquan
dc.contributor.authorSweatt, Jordan
dc.contributor.authorChirra, Bhagath
dc.contributor.authorMuñoz-Medina, Ricardo
dc.contributor.authorFarmer, Delaney E.
dc.contributor.authorKürti, László
dc.contributor.authorCannon, Carolyn L.
dc.date.accessioned2024-07-25T20:56:28Z
dc.date.available2024-07-25T20:56:28Z
dc.date.issued2024
dc.description.abstractThe increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has sparked global concern due to the dwindling availability of effective antibiotics. To increase our treatment options, researchers have investigated naturally occurring antimicrobial compounds and have identified MC21-A (C58), which has potent antimicrobial activity against MRSA. Recently, we have devised total synthesis schemes for C58 and its chloro-analog, C59. Here, we report that both compounds eradicate 90% of the 39 MRSA isolates tested [MIC90 and minimum bactericidal concentration (MBC90)] at lower or comparable concentrations compared to several standard-of-care (SoC) antimicrobials including daptomycin, vancomycin, and linezolid. Furthermore, a stable, water-soluble sodium salt of C59, C59Na, demonstrates antimicrobial activity comparable to C59. C59, unlike vancomycin, kills stationary-phase MRSA in a dose-dependent manner and completely eradicates MRSA biofilms. In contrast to vancomycin, exposing MRSA to sub-MIC concentrations of C59 does not result in the emergence of spontaneous resistance. Similarly, in a multi-step study, C59 demonstrates a low propensity of resistance acquisition when compared to SoC antimicrobials, such as linezolid and clindamycin. Our findings suggest C58, C59, and C59Na are non-toxic to mammalian cells at concentrations that exert antimicrobial activity; the lethal dose at median cell viability (LD50) is at least fivefold higher than the MBC90 in the two mammalian cell lines tested. A morphological examination of the effects of C59 on a MRSA isolate suggests the inhibition of the cell division process as a mechanism of action. Our results demonstrate the potential of this naturally occurring compound and its analogs as non-toxic next-generation antimicrobials to combat MRSA infections
dc.identifier.citationShah, K. N., Shah, P. N., Agobe, F. O., Lovato, K., Gao, H., Ogun, O., Hoffman, C., Yabe-Gill, M., Chen, Q., Sweatt, J., Chirra, B., Muñoz-Medina, R., Farmer, D. E., Kürti, L., & Cannon, C. L. (2024). Antimicrobial activity of a natural compound and analogs against multi-drug-resistant Gram-positive pathogens. Microbiology Spectrum, 12(3), e01515-22. https://doi.org/10.1128/spectrum.01515-22
dc.identifier.digitalshah-et-al-2024-antimicrobial-activity
dc.identifier.doihttps://doi.org/10.1128/spectrum.01515-22
dc.identifier.urihttps://hdl.handle.net/1911/117545
dc.language.isoeng
dc.publisherAmerican Society for Microbiology
dc.rightsExcept where otherwise noted, this work is licensed under a Creative Commons Attribution (CC BY) license.  Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleAntimicrobial activity of a natural compound and analogs against multi-drug-resistant Gram-positive pathogens
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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