Clinical breakpoint meropenem concentration modulate outer membrane vesicle production in enterotoxigenic Bacteroides fragilis

Saniya Kozhakhmetova, Ayazhan Bekbayeva, Elena V. Zholdybayeva, Tatyana Krivoruchko, Natalya Dashevskaya, E. B. Vinogradova, Nazira Kamzayeva, Zhanagul Khassenbekova, Almagul R. Kushugulova, Samat Kozhakhmetov

2025

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DOI 10.1007/s00203-025-04549-z
Data confidence 70 medium
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Abstract

Antibiotic concentrations at clinical breakpoint levels can influence bacterial physiology and virulence responses, yet their effects on outer membrane vesicle (OMV) production in anaerobic pathogens remain understudied. This study examined how breakpoint meropenem concentrations affect the ultrastructure, inflammatory responses, and OMV production of Bft + enterotoxigenic Bacteroides fragilis (ETBF) in a rat intra-abdominal infection model. Forty male Wistar rats were divided into negative control (n = 8), positive control (B. fragilis infection, n = 16), and experimental group (B. fragilis infection + meropenem at clinical breakpoint concentration 1.0 mg/L for 8 days, n = 16). Transmission electron microscopy, morphometric vesicle analysis, hematological studies, and qRT-PCR cytokine expression analysis were performed on days 8 and 16. Both B. fragilis infection groups showed systemic inflammation with critical hematocrit reduction to 27-28% compared to negative control (p ≤ 0.001). Breakpoint meropenem did not improve infection outcomes; bacterial load showed no significant differences, and OMV production demonstrated only a non-significant trend toward increase. However, the experimental group exhibited inflammation progression with significant elevation in IL-1α, IL-1β, and TNF-α expression by day 16 (p ≤ 0.05). Notably, OMV size distribution changed dramatically under breakpoint treatment, shifting toward significantly smaller vesicles (< 90 nm; Cliff's δ = -0.49, p ≤ 0.0001). The study demonstrates that breakpoint meropenem concentration triggers sustained stress response in enterotoxigenic B. fragilis, producing pronounced changes in OMV profile and suggesting a mechanism facilitating antibiotic resistance development.