Biology subjects

Dorjsuren, D.

Publications and source records attributed to Dorjsuren, D..

3 recordsLinked to original sources

bioRxiv2025

Breaking the Phalanx: Overcoming Bacterial Drug Resistance with Quorum Sensing Inhibitors that Enhance Therapeutic Activity of Antibiotics

Antibiotic-resistant bacterial infections loom over humanity as an increasingly deadly threat. There exists a dire need for new treatments, especially those that synergize with our existing arsenal of antibiotic drugs, to help overcome the gap in antibiotic efficacy and attenuate the development of new antibiotic resistance in the most dangerous pathogens. Quorum-sensing systems in bacteria drive the formation of biofilms, increase surface motility, and enhance other virulence factors, making these systems attractive targets for the discovery of novel antibacterials. Quorum-sensing inhibitors (QSIs) are hypothesized to synergize with existing antibiotics, making bacteria more sensitive to the effects of these drugs. In this study, we aimed to find the synergistic combinations between the QSIs and known antibiotics to combat the two deadliest hospital infections - Pseudomonas aeruginosa and Acinetobacter baumannii. We mined biochemical activity databases and literature to identify known, high-efficacy QSIs against these bacteria. We used these data to develop and validate a Quantitative Structure-Activity Relationship (QSAR) model for predicting QSI activity and then employed this model to identify new potential QSIs from the Inxight database of approved and investigational drugs. We then tested binary mixtures of the identified QSIs with 11 existing antibiotics using a combinatorial matrix screening approach with ten (five of each) clinical isolates of P. aeruginosa and A. baumannii. Amongst explored drug combinations, 22 exhibited a synergistic effect. Although no mixture inhibiting all the strains was found, piperacillin combined with ketoprofen, indomethacin, and piroxicam demonstrated the broadest antimicrobial action. We anticipate that further preclinical investigation of these combinations of novel repurposed QSIs with a known antibiotic may lead to novel clinical candidates. Table of Content Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/633658v3_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@17ee291org.highwire.dtl.DTLVardef@14cc242org.highwire.dtl.DTLVardef@65a9e2org.highwire.dtl.DTLVardef@743ac9_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2022

A comprehensive phenotypic screening strategy to identify modulators of cargo translocation by the bacterial Type IVB secretion system

Bacterial type IV secretion systems (T4SSs) are macromolecular machines that translocate effector proteins across multiple membranes into infected host cells. Loss of function mutations in genes encoding protein components of the T4SS render bacteria avirulent, highlighting the attractiveness of T4SSs as drug targets. Here, we designed an automated high-throughput screening approach for the identification of compounds that interfere with the delivery of a reporter-effector fusion protein from Legionella pneumophila into RAW264.7 mouse macrophages. Using a fluorescence resonance energy transfer (FRET)-based detection assay in a bacteria/macrophage co-culture format, we screened a library of over 18,000 compounds and, upon vetting compound candidates in a variety of in vitro and cell-based secondary screens, isolated several hits that efficiently interfered with biological processes that depend on a functional T4SS, such as intracellular bacterial proliferation or lysosomal avoidance, but had no detectable effect on L. pneumophila growth in culture medium, conditions under which the T4SS is dispensable. Notably, the same hit compounds also attenuated, to varying degrees, effector delivery by the closely related T4SS from Coxiella burnetii, notably without impacting growth of this organism within synthetic media. Together, these results support the idea that interference with T4SS function is a possible therapeutic intervention strategy, and the emerging compounds provide tools to interrogate at a molecular level the regulation and dynamics of these virulence-critical translocation machines. ImportanceMulti-drug-resistant pathogens are an emerging threat to human health. Since conventional antibiotics target not only the pathogen but also eradicate the beneficial microbiota, they often cause additional clinical complications. Thus, there is an urgent need for the development of "smarter" therapeutics that selectively target pathogens without affecting beneficial commensals. The bacterial type IV secretion system (T4SS) is essential for the virulence of a variety of pathogens but dispensable for bacterial viability in general and can, thus, be considered a pathogens Achilles heel. By identifying small molecules that interfere with cargo delivery by the T4SS from two important human pathogens, Legionella pneumophila and Coxiella burnetii, our study represents the first step in our pursuit towards precision medicine by developing pathogen-selective therapeutics capable of treating the infections without causing harm to commensal bacteria.

microbiology↗

bioRxiv2020

Robotic High-Throughput Biomanufacturing and Functional Differentiation of Human Pluripotent Stem Cells

Efficient translation of human induced pluripotent stem cells (hiPSCs) depends on implementing scalable cell manufacturing strategies that ensure optimal self-renewal and functional differentiation. Currently, manual culture of hiPSCs is highly variable and labor-intensive posing significant challenges for high-throughput applications. Here, we established a robotic platform and automated all essential steps of hiPSC culture and differentiation under chemically defined conditions. This streamlined approach allowed rapid and standardized manufacturing of billions of hiPSCs that can be produced in parallel from up to 90 different patient-and disease-specific cell lines. Moreover, we established automated multi-lineage differentiation to generate primary embryonic germ layers and more mature phenotypes such as neurons, cardiomyocytes, and hepatocytes. To validate our approach, we carefully compared robotic and manual cell culture and performed molecular and functional cell characterizations (e.g. bulk culture and single-cell transcriptomics, mass cytometry, metabolism, electrophysiology, Zika virus experiments) in order to benchmark industrial-scale cell culture operations towards building an integrated platform for efficient cell manufacturing for disease modeling, drug screening, and cell therapy. Combining stem cell-based models and non-stop robotic cell culture may become a powerful strategy to increase scientific rigor and productivity, which are particularly important during public health emergencies (e.g. opioid crisis, COVID-19 pandemic).

bioengineering↗