STEROIDS AS POTENTIAL ADJUVANTS: EFFECT ON EFFLUX SYSTEMS AND GENE EXPRESSION IN STAPHYLOCOCCUS  AUREUS

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22330%2F25%3A43932635" target="_blank" >RIV/60461373:22330/25:43932635 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

STEROIDS AS POTENTIAL ADJUVANTS: EFFECT ON EFFLUX SYSTEMS AND GENE EXPRESSION IN STAPHYLOCOCCUS  AUREUS

Popis výsledku v původním jazyce

The global rise of antibiotic resistance necessitates novel therapeutic strategies to restore the efficacy of existing antibiotics. One promising approach is the inhibition of bacterial efflux pumps, which contribute significantly to multidrug resistance in Staphylococcus aureus.In this study, we evaluated 26 endogenous steroidal hormones and neurosteroids, along with 30 synthetic derivatives, for their ability to modulate bacterial efflux activity. Using a combination of fluorescence-based ethidium bromide accumulation, broth microdilution, and checkerboard assays, we identified several compounds that enhanced antibiotic susceptibility in multidrug-resistant S. aureus. A structure-activity relationship (SAR) analysis revealed that specific modifications of the pregnanolone scaffold, particularly the introduction of polar substituents, markedly improved activity.Transcriptome analysis revealed that the most effective derivative significantly reduced the expression of genes involved in S. aureus virulence when administered alone or in combination with antibiotic adjuvant therapy. Cytotoxicity was assessed using the resazurin assay in human PBMCs, and receptor-mediated hormonal activity was evaluated via transactivation assays for estrogen, androgen, and progesterone receptors. Importantly, the most active derivatives were non-toxic and lacked measurable endocrine activity, suggesting a favorable pharmacological safety profile.These findings support the hypothesis that rationally designed steroidal scaffolds, especially pregnanolone-based derivatives, can act as competitive bacterial efflux pump inhibitors. Such compounds may serve as effective antibiotic adjuvants, offering a viable strategy to mitigate efflux-mediated resistance and enhance the therapeutic utility of existing antibiotics.

Název v anglickém jazyce

STEROIDS AS POTENTIAL ADJUVANTS: EFFECT ON EFFLUX SYSTEMS AND GENE EXPRESSION IN STAPHYLOCOCCUS  AUREUS

Popis výsledku anglicky

The global rise of antibiotic resistance necessitates novel therapeutic strategies to restore the efficacy of existing antibiotics. One promising approach is the inhibition of bacterial efflux pumps, which contribute significantly to multidrug resistance in Staphylococcus aureus.In this study, we evaluated 26 endogenous steroidal hormones and neurosteroids, along with 30 synthetic derivatives, for their ability to modulate bacterial efflux activity. Using a combination of fluorescence-based ethidium bromide accumulation, broth microdilution, and checkerboard assays, we identified several compounds that enhanced antibiotic susceptibility in multidrug-resistant S. aureus. A structure-activity relationship (SAR) analysis revealed that specific modifications of the pregnanolone scaffold, particularly the introduction of polar substituents, markedly improved activity.Transcriptome analysis revealed that the most effective derivative significantly reduced the expression of genes involved in S. aureus virulence when administered alone or in combination with antibiotic adjuvant therapy. Cytotoxicity was assessed using the resazurin assay in human PBMCs, and receptor-mediated hormonal activity was evaluated via transactivation assays for estrogen, androgen, and progesterone receptors. Importantly, the most active derivatives were non-toxic and lacked measurable endocrine activity, suggesting a favorable pharmacological safety profile.These findings support the hypothesis that rationally designed steroidal scaffolds, especially pregnanolone-based derivatives, can act as competitive bacterial efflux pump inhibitors. Such compounds may serve as effective antibiotic adjuvants, offering a viable strategy to mitigate efflux-mediated resistance and enhance the therapeutic utility of existing antibiotics.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10606 - Microbiology

Projekt

<a href="/cs/project/LX22NPO5103" target="_blank" >LX22NPO5103: Národní institut virologie a bakteriologie</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů