Biology subjects

Brink, J.

Publications and source records attributed to Brink, J..

4 recordsLinked to original sources

bioRxiv2026

Segmented regression to streamline semi-mechanistic pharmacodynamic modelling of antibiotic effects

Purpose Semi-mechanistic pharmacodynamic (PD) models quantify bacterial dynamics from time-kill (TK) assays, often showing multi-phasic kill and regrowth dynamics. Regrowth is typically captured with two subpopulations with distinct concentration-effect relationships. Since only total bacterial counts are observed, subpopulation dynamics must be inferred, causing identifiability issues, sensitivity to initial estimates, and model-testing burden. We aimed to establish an efficient and robust approach for developing semi-mechanistic PD models, demonstrated with 24-hour TK data for colistin against Pseudomonas aeruginosa. Methods A three-step workflow was developed: (1) log-transformed TK data were segmented into kill and regrowth phases, with linear regression estimating phase-specific slopes per concentration and replicate; (2) empirical slopes were pooled to derive concentration-effect relationships; (3) selected relationships and parameter estimates were incorporated into a semi-mechanistic PD model. Results Segmented regression captured kill and regrowth slopes at all concentrations. Slope saturation with increasing colistin and consistently weaker drug effect during regrowth indicated a less susceptible subpopulation, motivating a two-subpopulation model. The semi-mechanistic model adequately described bacterial dynamics at all concentrations, with parameters comparable to Step 2. Conclusion This three-step workflow enables efficient and robust identification of concentration-effect relationships, reducing model testing and computational burden for streamlined semi-mechanistic antibiotic PD model development.

pharmacology and toxicology↗

bioRxiv2026

Unmasking Glycoforms: Lectin-Based Profiling and Functional Implications of Targeted Glycosylation Knockouts in CHO Cells

Monoclonal antibody (mAb) glycosylation is a critical quality attribute that is difficult to rationally engineer and rapidly assess during cell line development. Here, we investigate whether cell-surface glycosylation can serve as a predictive indicator of mAb product glycosylation following targeted glycogene engineering in CHO cells. Five key glycogenes (COSMC, FUT8, B4GALT1, ST3GAL4, ST6GAL1) were investigated in two mAb-producing CHO cell lines. Product glycan analysis revealed consistent, gene-specific effects across hosts, including loss of core fucosylation, and tuneable galactosylation and sialylation. Lectin-based surface profiling reliably reflected product outcomes for COSMC and FUT8 modifications but showed limited predictive power for galactosylation and 2,3-sialylation, highlighting glycosylation pathway redundancy and context dependence. This study provides the first systematic, cross-cell line evaluation of lectin-based cell-surface glycan profiling as a predictor of mAb product glycosylation, establishing its practical utility and inherent limitations for CHO glycoengineering workflows. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/724788v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@6d5cfborg.highwire.dtl.DTLVardef@1f38e0aorg.highwire.dtl.DTLVardef@f25fa2org.highwire.dtl.DTLVardef@64a0dc_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

A Novel Hollow Fiber Infection Model (HFIM) for Antiviral PK/PD studies of CMV infection.

The hollow fiber infection model (HFIM) is a translational in vitro model that links time-varying human pharmacokinetic profiles to the associated viral dynamic responses, from which pharmacokinetic/pharmacodynamic (PK/PD) targets can be derived. Establishing such targets is essential for antiviral dose selection and optimization. This is particularly important for cytomegalovirus (CMV) infection treatment, which primarily affects vulnerable patient populations. PK/PD targets for ganciclovir, the first-line drug for treatment, are not yet defined. The lack of an undefined PK/PD target makes dose optimization challenging and may result in suboptimal exposure, prolonged toxicity, and the emergence of resistance. For the first time, we have demonstrated the use of a low-cost hemodialyzer hollow fiber cartridge with application for CMV infection using ganciclovir. We have established a system that 1) supports CMV culture for PD analysis, 2) reproduces a clinically relevant ganciclovir PK profile, and 3) maintains consistent drug exposure in the infected cells, allowing reliable PK/PD analysis. Quantitative methods such as tissue culture infectious dose 50% (TCID50) and quantitative PCR were used to assess both active virus replication and genome copies production. Ganciclovir PK was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This validation study serves as a fundamental step that can allow further PK/PD studies for ganciclovir and other antiviral agents that is still largely understudied. Consequently, this model could provide an affordable and practical platform for establishing clinically relevant PK/PD targets and guide treatment optimization.

pharmacology and toxicology↗

bioRxiv2021

Antibiotic breakdown by susceptible bacteria enhances the establishment of β-lactam resistant mutants

For a better understanding of the evolution of antibiotic resistance, it is imperative to study the factors that determine the initial establishment of mutant resistance alleles. In addition to the antibiotic concentration, the establishment of resistance alleles may be affected by interactions with the surrounding susceptible cells from which they derive, for instance via the release of nutrients or removal of the antibiotic. Here, we investigate the effects of social interactions with surrounding susceptible cells on the establishment of Escherichia coli mutants with increasing {beta}-lactamase activity (i.e. the capacity to hydrolyze {beta}-lactam antibiotics) from single cells under the exposure of the antibiotic cefotaxime on agar plates. We find that mutant establishment probability is increased in the presence of susceptible cells due to the active breakdown of the antibiotic, but the rate of breakdown by the susceptible strain is much higher than expected based on its low enzymatic activity. A detailed theoretical model suggests that this observation can be explained by cell filamentation causing delayed lysis. While susceptible cells may hamper the spread of higher-resistant {beta}-lactamase mutants at relatively high frequencies, our findings show that they could promote establishment during their emergence.

evolutionary biology↗