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

Result code in 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>

Result on the web

—

DOI - Digital Object Identifier

—

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

—

Czech description

—

Type

O - Miscellaneous

CEP classification

—

OECD FORD branch

10606 - Microbiology

Project

<a href="/en/project/LX22NPO5103" target="_blank" >LX22NPO5103: National Institute of Virology and Bacteriology</a><br>

Continuities

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

Publication year

2025

Confidentiality

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