Biology subjects

Brenzinger, S.

Publications and source records attributed to Brenzinger, S..

7 recordsLinked to original sources

bioRxiv2026

Human-targeted drugs extensively reshape regulatory networks controlling virulence and antibiotic resistance in Salmonella Typhimurium

Human-targeted drugs are increasingly recognized to affect bacterial physiology, yet their impact beyond growth inhibition, and the underlying molecular mechanisms, remain poorly understood. Here, we systematically mapped how chemically diverse host-associated compounds influence virulence and intrinsic antibiotic resistance in Salmonella enterica serovar Typhimurium. Using a high-throughput reporter approach, we quantified transcriptional response of 26 key stress promoters in Salmonella against 2,415 compounds, including FDA-approved drugs, food-derived molecules, and human metabolites. We found that non-antibiotic compounds induce transcriptional responses distinct from those elicited by antibiotics, uncovering a regulatory shift from general stress responses to compound-specific regulation driven by ligand-responsive MarR- and TetR-family regulators. In particular, more than 200 non-antibiotic drugs modulate virulence or intrinsic resistance pathways through the central regulators SlyA or RamR, respectively. By integrating our large-scale dataset with machine learning, we further defined chemical features associated with ramA transcriptional activation in Salmonella, and predicted ~200 additional candidate inducers of intrinsic antibiotic resistance in this pathogen. Together, our results uncovered a large and previously unrecognized chemical landscape that reshapes bacterial stress responses through ligand-responsive regulatory mechanisms, with implications for how host-associated compounds influence pathogen virulence and antibiotic resistance.

microbiology↗

bioRxiv2025

ICP1 bacteriophage treatment antagonizes colonization of the zebrafish larval intestine by Vibrio cholerae

Outbreaks of cholera pose a major threat to human health. Currently, antibiotics are the most effective treatment against the causative agent, the bacterium Vibrio cholerae. However, the use of antibiotics eventually leads to the emergence of resistant strains, which necessitates the need for alternative approaches. The use of bacteriophages to target the infection by antibiotic resistant bacteria is one promising alternative. While clearance of Vibrio cholerae with the use of phages has been performed on several animal models, none of these models are natural hosts of V. cholerae. Therefore, we set out to investigate the interaction between V. cholerae and bacteriophage ICP1 both in vitro and in vivo in a natural host, the zebrafish model, Danio rerio. To study the interplay between host, bacteria and phages we used a combination of light and ultrastructural imaging techniques, including confocal fluorescence microscopy, serial block face scanning electron microscopy (EM) imaging and cryogenic EM, which allowed us to investigate both the colonization process by V. cholerae and clearance by the ICP1 bacteriophage. In addition, we determined the effects of the microbiome on this treatment by using germ-free, conventionalized and monoassociated zebrafish larvae as a host. Independent of the presence and composition of microbiomes used here, V. cholerae efficiently colonized the larval intestine. Finally, we demonstrate significant in vivo clearance of V. cholerae N16961-dsRED by ICP1, underscoring the role of phage-bacteria dynamics in shaping pathogen colonization within the zebrafish larval host. SIGNIFICANCECholera remains a life-threatening disease that causes recurring outbreaks and significant mortality, particularly in developing and conflict-affected regions. As antimicrobial resistance continues to rise, there is an urgent need to better understand the ecological and microbial dynamics that govern Vibrio cholerae colonization and persistence. This research investigates how V. cholerae interacts with bacteriophages, the host environment, and the resident microbiota within a natural vertebrate host, offering new insights into the factors that influence pathogen clearance and shaping of the gut ecosystem during infection. The powerful combination of serial block-face scanning and cryogenic electron microscopy, fluorescence microscopy, and traditional colony/plaque counting methods revealed previously unobserved aspects of the interplay between host, pathogen, phages, and the microbiome, highlighting phage-driven clearance of V. cholerae during colonization.

microbiology↗

bioRxiv2023

The antiphage defense system CBASS controls resistance and enables killing by antifolate antibiotics in Vibrio cholerae

Toxic bacterial modules, in particular toxin-antitoxin (TA) systems, have been long sought-after for their antimicrobial potential, although with limited success1-6. Here we show that the cyclic-oligonucleotide-based antiphage signaling system (CBASS), another example of a toxic module, increases sensitivity to well-established antifolate antibiotics, interferes with their synergy, and ultimately enables bacterial lysis by antifolates - classic bacteriostatic antibiotics, in Vibrio cholerae. We propose a molecular mechanism for the CBASS-antifolate interaction based on onset of cyclic-oligonucleotide production by the nucleotidyltransferase DncV upon folate depletion by antifolates. CBASS-antifolate interaction is specific to CBASS systems with closely related nucleotidyltransferases and similar folate binding. Altogether, our findings illustrate that toxic modules, such as the antiphage defense CBASS system, can dramatically impact antibiotic activity, and open the possibility that endogenous metabolites could also act as triggers/silencers of toxic modules under stress beyond antibiotic treatment, such as during phage infection, biofilm formation or disease environments.

microbiology↗

bioRxiv2022

A flexible and efficient microfluidics platform for the characterization and isolation of novel bacteriophages

Bacteriophages are viruses that infect bacteria. This property makes them highly suitable for varied uses in industry or in the development of the treatment of bacterial infections. However, the conventional methods that are used to isolate and analyze these bacteriophages from the environment are generally cumbersome and time-consuming. Here, we adapted a high-throughput microfluidic setup for long-term analysis of bacteriophage-bacteria interaction and demonstrate isolation of phages from environmental samples.

microbiology↗

bioRxiv2018

Structural and proteomic changes in viable but non-culturable Vibrio cholerae

Aquatic environments are reservoirs of the human pathogen Vibrio cholerae O1, which causes the acute diarrheal disease cholera. Upon low temperature or limited nutrient availability, the cells enter a viable but non-culturable (VBNC) state. Characteristic of this state are an altered morphology, low metabolic activity and lack of growth under standard laboratory conditions. Here, for the first time, the cellular ultrastructure of V. cholerae VBNC cells raised in natural waters was investigated using electron cryo-tomography complemented by comparison of the proteomes and the peptidoglycan composition of LB overnight culture and VBNC cells. The extensive remodeling of the VBNC cells was most obvious in the passive dehiscence of the cell envelope, resulting in improper embedment of flagella and pili. Only minor changes of the peptidoglycan and osmoregulated periplasmic glucans were observed. Active changes in VBNC cells included the production of cluster I chemosensory arrays and change of abundance of cluster II array proteins. Components involved in iron acquisition and storage, peptide import and arginine biosynthesis were overrepresented in VBNC cells, while enzymes of the central carbon metabolism were found at lower levels. Finally, several pathogenicity factors of V. cholerae were less abundant in the VBNC state, potentially limiting their infectious potential.

microbiology↗

bioRxiv2018

γ-proteobacteria eject their polar flagella under nutrient depletion, retaining flagellar motor relic structures

Bacteria switch only intermittently to motile planktonic lifestyles under favourable conditions. Under chronic nutrient deprivation, however, bacteria orchestrate a switch to stationary phase, conserving energy by altering metabolism and stopping motility. About two-thirds of bacteria use flagella to swim, but how bacteria deactivate this large-molecular machine remains poorly studied. Here we describe the previously unreported ejection of polar sodium-driven motors by {gamma}-proteobacteria. We show that these bacteria eject their flagella at the base of the flagellar hook when nutrients are depleted, leaving a relic of a former flagellar motor in the outer membrane. Subtomogram averages of the full motor and relic reveal that this is an active process, as a plug protein appears in the relic, likely to prevent leakage across their outer membrane. We show that this is a widespread phenomenon demonstrated by the appearance of relic structures in varied {gamma}-proteobacteria including Plesiomonas shigelloides, Vibrio cholerae, Vibrio fischeri, Shewanella putrefaciens and Pseudomonas aeruginosa.

microbiology↗

bioRxiv2017

An open-source cryo-storage solution

The field of cryo-electron microscopy is a rapidly growing method in structural biology. With this development, access to cryo-EM facilities becomes a bottleneck that results in long wait times between sample preparation and data acquisition. To improve sample storage, we developed a cryo-storage system with a more efficient and larger storage capacity that enables cryo-sample storage in a highly organized manner. This system is simple to use, cost-effective and easily adaptable for any type of grid box and storage dewar and any size cryo-EM laboratory.

molecular biology↗