Biology subjects

Hollander, J.

Publications and source records attributed to Hollander, J..

3 recordsLinked to original sources

bioRxiv2026

Experimental evolution of collective β-lactam resistance in Escherichia coli via activation of a dormant outermembrane porin

Understanding the mechanisms that drive antibiotic resistance is relevant for both evolutionary theory and the design of effective drug therapies. A specific challenge are collective resistance mechanisms, where bacterial populations survive drug concentrations that kill individual bacteria. Here, we explore the evolvability of collective resistance mechanisms in bacterial strains expressing antibiotic-degrading {beta}-lactamases with different levels of privatization. Four strains of Escherichia coli, with or without outermembrane porin OmpF to affect drug permeability and expressing either a low or high-activity periplasmic {beta}-lactamase, were subjected to lineage selection in a gradient of the drug cefotaxime. Strains with a low-activity enzyme increased cell-level resistance, while strains with low permeability, and hence a more private {beta}-lactamase function, increased collective resistance. Remarkably, increased collective resistance in the strain with a private high-activity {beta}-lactamase came with decreased cell-level resistance. This tradeoff was primarily caused by the activation of a dormant outermembrane porin, NmpC, via the excision of an insertion sequence. Increased drug permeability through NmpC explained both its lower cell-level resistance and its greater collective resistance through faster drug removal and growth recovery via enhanced filamentation at high cell density. The recovery advantage of the NmpC mutant also explained its initial invasion within the ancestral population, suggesting that drug permeability is a readily evolvable collective-resistance mechanism in bacteria with high-activity {beta}-lactamases. Our findings highlight the role of filamentation and drug permeability in {beta}-lactamase-mediated collective resistance to these widely used drugs.

evolutionary biology↗

bioRxiv2023

Gibberellin transport affects (lateral) root growth through HY5 during Far-Red light enrichment.

Plants compete for light by growing taller than their nearest competitors. This is part of the shade avoidance syndrome and is a response to an increase of Far-Red light (FR) reflected from neighboring leaves. The root responds to this shoot-sensed FR cue by reducing lateral root emergence. It is well-established that the plant hormone Gibberellic Acid (GA) is involved in supplemental FR-induced shoot elongation. Although GA is also transported from shoot to root, its role in regulating lateral root growth is unclear. We show via GA manipulations, both chemical and genetic, that GA modulates the lateral root reduction induced by shoot-sensed FR enrichment. Using the FRET-based GA biosensor GPS1, we observed detailed GA changes in the root upon shoot exposure to FR enrichment and when GA was supplied to the shoot. Supplying GA to the shoot also mitigated the FR-enrichment root phenotype, indicating a functional link between GA and changes in root development in response to shoot-sensed FR. The regulatory role of GA in root growth appears to be partially dependent upon the role of ELONGATED HYPOCOTYL 5 (HY5), a light-responsive transcription factor that regulates root growth. Shoot-to-root transported GA4 led to an increase in HY5 protein levels in the lateral root primordia. HY5 then repressed auxin signaling to repress lateral root growth. Our data unveil a novel way in which hormone and light signaling coordinate development across spatial scales by adjusting (lateral) root growth from above-ground FR light signals.

plant biology↗

bioRxiv2019

Targeting the dysfunctional mitochondrial respiration in drug resistant B-cell acute lymphoblastic leukemia

Reprogramming of cellular pathways is a crucial mechanism of drug resistance and survival in refractory acute lymphoblastic leukemia (ALL) cells. In the present study, we performed an unbiased gene expression analysis and identified a dysfunctional mitochondrial respiration program in drug-resistant ALL cells grown in a co-culture system with bone marrow stromal cells (BMSC). Specifically, the activity of the complexes within the electron transport chain was significantly downregulated, correlated with decreased mitochondrial mass and ATP production in drug-resistant ALL cells. To validate mitochondrial respiration as a druggable target, we utilized pyrvinium pamoate (PP), a known inhibitor of mitochondrial respiration and documented its anti-leukemic activity in several ALL cell lines grown alone or in co-culture with BMSC. To increase the bioavailability profile of PP, we successfully encapsulated PP in a nanoparticle drug delivery system and demonstrated that it retained its anti-leukemic activity in a hemosphere assay. PP anti-leukemic activity was decreased by the addition of sodium pyruvate, and furthermore, PP was found to have an additive anti-leukemic effect when used in combination with rotenone, a mitochondrial complex I inhibitor with activity similar to PP on the mitochondrial respiration. Importantly, PPs cell death activity was found to be specific for leukemic cells as primary normal immune cells were resistant to PP-mediated cell death. In conclusion, we have demonstrated that PP is a novel therapeutic lead compound that counteracts the respiratory reprogramming found in refractory ALL cells.

cancer biology↗