Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/624577

Pharmacodynamics of linezolid-plus-fosfomycin against vancomycin-susceptible and -resistant enterococci in vitro and in vivo of a Galleria mellonella larval infection model

Qi, C. f.·Xu, S. l.·Wu, M. m.·Zhu, S.·Liu, Y.-Y.·Huang, H.·Zhang, G. j.·Li, J.·Huang, X. h.
View original source ↗Export metadata ↓

Abstract

ObjectiveTo explore the in vitro and in vivo antibacterial activity of linezolid/fosfomycin combination against vancomycin-susceptible and -resistant enterococci (VSE and VRE), providing theoretical basis for the treatment of VRE.\n\nMethodsThe checkerboard method and time-kill curve study were used to evaluate the synergistic effect of linezolid combined with fosfomycin against VSE and VRE. The transmission electron microscopy (TEM) was employed to observe the bacterial cell morphology followed by each drug alone and in combination, elucidating the possible result of antibiotic combination therapy. The Galleria mellonella infection model was constructed to demonstrate the in vivo efficacy of linezolid plus fosfomycin for VSE and VRE infection.\n\nResultsThe fractional inhibitory concentration index (FICI) values of all strains suggested that linezolid showed synergy or additivity in combination with fosfomycin against five of the six strains. Time-kill experiments demonstrated that the combination of linezolid-fosfomycin at 1xMIC or 2xMIC led to higher degree of bacterial killing without regrowth for all isolates tested than each monotherapy. TEM imaging showed that the combination treatment damaged the bacterial cell morphology more obviously than each drug alone. In the Galleria mellonella infection model, the enhanced survival rate of the combination treatment was revealed compared to linezolid monotherapy (P<0.05).\n\nConclusionsOur data manifest that the combination of linezolid and fosfomycin may be a possible therapeutic regimen for VRE infection. The combination displays excellent bacterial killing and inhibits amplification of fosfomycin-resistant subpopulations.

Explore related subjects

pharmacology and toxicologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Qi, C. f., Xu, S. l., Wu, M. m., Zhu, S., Liu, Y.-Y., Huang, H., Zhang, G. j., Li, J., Huang, X. h.. 2019-05-01. Pharmacodynamics of linezolid-plus-fosfomycin against vancomycin-susceptible and -resistant enterococci in vitro and in vivo of a Galleria mellonella larval infection model. https://doi.org/10.1101/624577

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Lipid-ASO therapeutics exhibit differential tissue targeted delivery upon systemic or local CNS administration

Antisense oligonucleotides (ASOs) are a powerful therapeutic modality, but their full potential is hindered by pharmacokinetic properties that affect tissue and cellular delivery. Lipid conjugation is increasingly used to modulate ASO's biodistribution and promote extrahepatic activity, yet lipid dependent effects on in vivo functional delivery, particularly in the central nervous system (CNS), remain less explored. Here, we performed a side by side in vivo comparison of cholesterol, palmitic acid (C16:0), docosanoic acid (C22:0), and eicosapentaenoic acid (C20:5) conjugated to a fully phosphorothioated 3 10 3 LNA gapmer ASO targeting the Malat1 long non coding RNA. Lipid-ASO conjugates were administered systemically or locally in the brain of mice and evaluated for tissue level and cellular level distribution by imaging, qPCR and single-cell RNA sequencing, simultaneously annotating cell origin and global transcriptional changes within the cell. Following systemic administration in mice, lipid conjugation improved overall multi organ efficacy compared to unconjugated ASO, but with pronounced tissue specific differences. Single cell sequencing of liver and heart transcriptomes revealed lipid dependent cellular uptake patterns and transcriptional responses distinct from administration of unconjugated ASO. After intracerebroventricular administration, selected fatty acid conjugates enhanced silencing in deep brain regions such as the striatum, whereas cholesterol conjugation impaired functional delivery despite increased CNS retention. Light-sheet microscopy showed restricted parenchymal penetration of cholesterol ASOs compared with broader but heterogeneous distribution of palmitic acid conjugate. Together, these findings demonstrate that lipid identity critically determines ASO efficacy, productive cellular uptake, and regional CNS engagement, emphasizing the need for context specific lipid design in ASO therapeutic development.

pharmacology and toxicology↗
bioRxiv2026

Novel Dissymmetric Ionizable Lipid-Assembled Lipid Nanoparticles for Delivery of Ferroptosis-Related siRNA in Diabetic Treatment

Small interfering RNA (siRNA) enables precise post-transcriptional gene silencing for refractory diseases, yet its clinical translation remains limited by the lack of safe and efficient delivery vectors. Inspired by the dissymmetric alkyl chain architecture of natural membrane phospholipids, we designed and synthesized 34 novel ionizable lipids with dissymmetric hydrophobic tails and formulated them into lipid nanoparticles (LNPs). Through systematic physicochemical and biological assessments, we established clear structure-activity relationships and identified two lead LNPs (O14-LNP, H18a-LNP) with superior endosomal escape capacity, enhanced in vivo gene silencing potency, and favorable biosafety relative to the clinical benchmark MC3-LNP. In both streptozotocin-induced and spontaneous db/db type 2 diabetes (T2D) mouse models, lead LNPs delivering ferroptosis-related siRNAs effectively ameliorated glucose and lipid metabolic disorders, restored islet function, and alleviated hepatic steatosis. This study not only lays a theoretical foundation for the rational design of novel ionizable lipids, but also validates the therapeutic potential of siRNA therapy targeting ferroptosis, providing a versatile delivery platform and targeted therapeutic strategy for the treatment of T2D.

pharmacology and toxicology↗
bioRxiv2019

Peritubular Macrophages and Spermatogonia are Sequentially Increased in the Testis of Rats After Mono-(2-Ethylhexyl) Phthalate Exposure

AO_SCPLOWBSTRACTC_SCPLOWPeripubertal exposure to the phthalate metabolite mono-(2-ethylhexyl) phthalate (MEHP) in rodents causes testicular inflammation, spermatocyte apoptosis, and disruption of the blood-testis barrier. The MEHP-induced inflammation response includes an infiltration of macrophages and neutrophils to the testes, although the cause and purpose of this response is unknown. Recently, a population of testicular macrophages phenotypically distinct from those resident in the interstitium was described in mice. Testicular peritubular macrophages aggregate near the spermatogonial stem cell niche and are believed to stimulate their differentiation. We hypothesized that if testicular peritubular macrophages do indeed stimulate spermatogonial differentiation, MEHP exposure would result in an increase of peritubular macrophages to stimulate the replacement of lost spermatocytes. Male rats were exposed to 700 mg/kg MEHP or corn oil (vehicle control) via oral gavage at PND 28 and euthanized at 48 hours, 1 week, or 2 weeks later. Tubules were stained with immunofluorescent markers for macrophages and undifferentiated spermatogonia. Peritubular macrophages were observed in rat testis similar to those previously described in mice: MHC-II+ cells on the surface of seminiferous tubules with heterogeneous morphology. Quantification of MHC-II+ cells revealed that, unlike in the mouse, their numbers did not increase through puberty. MEHP increased macrophage presence by six-fold 48-hours after exposure and remained elevated by two-fold two weeks after exposure. An increase of differentiating spermatogonia occurred two weeks after MEHP exposure. Taken together, our results suggest that peritubular macrophages play a crucial role in the testis response to acute injury and the subsequent recovery of spermatogenesis.\n\nSummary SentencePhthalate-induced testicular injury results in an increase of specialized peritubular macrophages that may assist in the recovery of spermatogenesis.

pharmacology and toxicology↗