Publications by authors named "Ioerger T"
Although not currently in the infectious disease spotlight, there is still a pressing need for new agents to treat tuberculosis caused by . As there is an ever-increasing amount of clinical resistance to the current drugs, ideally new drugs would be found against novel targets to circumvent pre-existing resistance. A phenotypic growth screen identified a novel singleton, , as an inhibitor of growth.
View Article and Find Full Text PDFUnlabelled: (Mtb) exhibits an impressive ability to adapt to rapidly changing environments, despite its genome's apparent stability. Recently, phase variation through indel formation in homopolymeric tracts (HT) has emerged as a potentially important mechanism promoting adaptation in Mtb. This study examines the impact of common phase variants associated with the ESX-1 type VII secretion system, focusing on a highly variable HT upstream of the ESX-1 regulatory factor, .
View Article and Find Full Text PDFUnlabelled: ) is a clinically significant pathogen and a highly genetically diverse species due to its large accessory genome. The functional consequence of this diversity remains unknown mainly because, to date, functional genomic studies in have been primarily performed on reference strains. Given the growing public health threat of infections, understanding the functional genomic differences among clinical isolates can provide more insight into how its genetic diversity influences gene essentiality, clinically relevant phenotypes, and importantly, potential drug targets.
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- This study explored how Mycobacterium kansasii, which causes lung disease, may be transmitted through environmental sources, particularly water, by examining patients in Taiwan from 2015-2017.
- Researchers analyzed sputum samples and used advanced methods to assess the genetic similarities of M. kansasii strains.
- The results showed that individuals living near two specific water purification plants were at a higher risk for infections, emphasizing the need for more research on environmental factors linked to this disease.
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- The growing issue of antimicrobial resistance highlights the urgent need for new treatments against Mycobacterium tuberculosis (Mtb), leading researchers to explore callyaerins, a class of unique hydrophobic cyclopeptides, as potential anti-tubercular agents.
- Callyaerins are effective against various strains of Mtb, including those resistant to existing antibiotics, showing minimal harm to human cells and strong intracellular activity.
- Studies reveal that callyaerins target a specific membrane protein in Mtb, Rv2113, causing significant disturbances in vital cellular processes like lipid synthesis and DNA repair, indicating that even non-essential proteins could be promising targets for new antimycobacterial drugs.
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- CRISPR interference (CRISPRi) is used to identify chemical-genetic interactions (CGIs) by determining how genes react to antibiotic exposure, helping discover potential drug targets and resistance mechanisms.
- The efficiency of different sgRNAs influences the growth rate of CRISPRi mutants, but optimal sgRNA for detecting drug interactions doesn't always correspond to the most efficient one. There exists a non-linear relationship between sgRNA strength and drug sensitivity.
- The CRISPRi-DR statistical method improves analysis by integrating sgRNA efficiencies with drug concentrations, showing better precision on complex datasets relative to other methods while effectively identifying gene interactions in microorganisms like Mycobacterium tuberculosis and E. coli.
Article Synopsis
- Finding genes that work together in RNA-Seq studies can be challenging, as existing methods often focus on quantitative similarities rather than biological significance.
- * The proposed Dual ICA methodology analyzes gene and condition data separately using Independent Component Analysis to identify "interacting modules" with strong associations.
- * This approach outperforms traditional clustering methods by not only aligning with known biological pathways but also revealing functional relationships between genes and conditions.
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- * RNase E affects the degradation rates of transcripts from around 89% of protein-coding genes in Mycolicibacterium smegmatis, with a more significant impact on leadered transcripts compared to leaderless ones.
- * The researchers found that RNase E has a preference for cleaving RNA in C-rich regions and identified precise cleavage sites in Mycobacterium tuberculosis, highlighting RNase E's significant influence on its transcriptome.
Article Synopsis
- The bacterium that causes tuberculosis, a significant global health issue, is responsible for over a million deaths annually, highlighting the need for shorter and simpler treatment options.
- Research shows that this bacterium can adapt its metabolism during nutrient starvation, which occurs during infection, allowing it to withstand standard antibiotic treatments.
- A genetic study identified 220 mutant strains of the bacterium with different responses to key antibiotics, revealing several genes that may serve as potential therapeutic targets to improve treatment effectiveness.
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- The study addresses the urgent issue of drug-resistant tuberculosis, emphasizing the necessity for new drug candidates to improve treatment options.
- Researchers discovered a potent compound, (4-benzylpiperidin-1-yl)(1-(5-phenyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone, through high-throughput screening, which showed effectiveness against both drug-resistant and drug-susceptible strains of TB.
- Analysis of resistant mutant strains identified mutations in the DprE1 gene, suggesting a new avenue for drug development and highlighting the potential of the novel oxadiazole structure as a valuable tool in TB treatment.
Article Synopsis
- * Different sgRNAs can deplete target proteins to varying extents, influencing cellular growth and drug response; however, the most efficient sgRNAs aren't always the best for detecting drug synergies.
- * The new CRISPRi-DR statistical method combines sgRNA efficiencies with drug concentrations in a modified dose-response model to improve the identification of gene-drug interactions, outperforming some existing methods in terms of precision.
Article Synopsis
- Phase variation through short insertions and deletions (INDELs) in genomic homopolymeric tracts (HT) can regulate gene expression in pathogenic bacteria, but its role in Mycobacterium tuberculosis complex (MTBC) adaptation is not well studied.
- Analyzing 31,428 diverse clinical isolates, researchers found that 12.4% of repeated INDEL events involved phase-variants within HTs, which represent a small fraction of the genome.
- They confirmed that a specific phase-variant significantly affects the expression of a key gene related to virulence, suggesting that phase variation may help MTBC toggle between immune recognition and host survival.
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- The immune system combats chronic infections by producing harmful compounds and depriving pathogens of vital nutrients like iron and zinc.
- The intramembrane protease Rip1 helps pathogens adapt to these stresses by cleaving certain proteins and is critical for survival in low-iron and low-zinc conditions, similar to what the immune system enforces.
- Research reveals that Rip1 works alongside the regulatory protein SigL to manage metal balance, suggesting that this pathway is crucial for pathogen growth in nutrient-scarce environments during infection.
Article Synopsis
- * The study focused on understanding how the bacterium adapts to nutrient starvation during infection, which helps it survive against antibiotics like rifampin and isoniazid, by conducting a genetic screen to identify related genes.
- * Researchers discovered 220 mutants with different antibiotic responses under nutrient-rich conditions and 82 mutants under nutrient-starved conditions, revealing promising genetic targets that may contribute to more effective and shorter TB treatments.
A mutant fitness assay identifies bacterial interactions in a model ocean hot spot.
Proc Natl Acad Sci U S A
March 2023
Article Synopsis
- The study focuses on the interactions of bacteria in the phycospheres around phytoplankton, which are important for ocean productivity, by identifying key genes involved in these interactions.
- Researchers used a transposon mutant library of a specific bacterium alongside phytoplankton to see how these bacteria interact in the presence of other species, uncovering complex competition and cooperation among them.
- Findings revealed over 200 nonessential genes that help bacteria manage competition for resources like nitrogen and organic compounds, highlighting the adaptations needed to thrive in dynamic microscopic environments.
Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against . To ensure compound supply for further development, we studied myxovalargin biosynthesis in detail enabling production via fermentation of a native producer.
View Article and Find Full Text PDFAlternative mode-of-inhibition of clinically validated targets is an effective strategy for circumventing existing clinical drug resistance. Herein, we report 1,3-diarylpyrazolyl-acylsulfonamides as potent inhibitors of HadAB/BC, a 3-hydroxyl-ACP dehydratase complex required to iteratively elongate the meromycolate chain of mycolic acids in (). Mutations in compound -resistant mutants mapped to HadC (Rv0637; K157R), while chemoproteomics confirmed the compound's binding to HadA (Rv0635), HadB (Rv0636), and HadC.
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- The study focuses on a rapidly growing non-tuberculous mycobacterium (NTM) that causes various infections, which are hard to treat due to antibiotic resistance.
- Researchers used transposon sequencing to identify ~362 essential genes for the bacterium's in vitro growth, discovering vulnerabilities that could guide new drug development.
- One key finding is the importance of the enzyme PBP-lipo, which affects cell wall synthesis; targeting PBP-lipo can enhance the efficacy of certain antibiotics against the bacterium, making it a promising drug target for treating infections.
Article Synopsis
- Genetic diversity in Mycobacterium tuberculosis (M. tuberculosis) influences infection outcomes and public health interventions like vaccination, with certain strains showing traits such as hypervirulence and vaccine escape.
- A study used a molecular barcoding strategy to analyze growth dynamics of diverse M. tuberculosis strains in a mouse model, revealing that the mL2 sublineage exhibits unique growth patterns and resistance to Bacillus Calmette-Guerin (BCG) vaccine protection.
- Investigations into mL2 strains led to the identification of genetic changes linked to stress response and regulatory genes, which may explain their clinical traits and success in spreading.
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- * This study explored the relationship between Mtb's carbon metabolism and drug interactions by using gene knockdown mutants to analyze the effects of common antitubercular drugs, revealing that the bacterial metabolic state significantly influences drug efficacy.
- * The researchers identified ways to enhance rifampicin effectiveness when Mtb grows on cholesterol, providing insights that could help improve drug combinations and understanding of how laboratory results relate to real-world infection scenarios.
Article Synopsis
- - Trehalose is crucial for the survival of Mycobacterium tuberculosis, which can both synthesize it and absorb it from outside sources; its transport involves the ABC transporter LpqY-SugA-SugB-SugC across the cytoplasmic membrane but remains unclear through the mycomembrane.
- - Researchers utilized the compound 6-azido trehalose to identify resistant M. tuberculosis mutants, discovering that mutations linked to resistance occurred in the PPE family protein PPE51, which is part of the mycomembrane and aids in transporting small molecules.
- - A mutant strain lacking the ppe51 gene failed to utilize trehalose as a carbon source, confirming that PPE51 is essential for the
Article Synopsis
- * Researchers used a genetically diverse group of mice, known as the Collaborative Cross (CC), along with a library of bacterial mutants, to explore the relationship between bacterial genetics and host immunity.
- * Findings indicated that different mouse strains showed significant differences in their susceptibility to infection and immune responses, highlighting specific host-pathogen interactions that affect disease outcomes.
New drugs and new targets are urgently needed to treat tuberculosis. We discovered that d-phenylalanine-benzoxazole displays potent antibacterial activity against () in multiple media and in macrophage infections. A metabolomic profiling indicates that has a unique mechanism of action.
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- - TnSeq is a method used to study gene functions in bacteria by analyzing transposon insertions, which disrupt gene activity and help identify critical genes for survival and potential drug targets.
- - Two common transposons used in TnSeq are Himar1, which targets specific DNA sequences, and Tn5, which has a broader insertion range, resulting in different effects on gene function.
- - The chapter introduces Transit, a Python software package developed to handle the noisy data from TnSeq experiments, providing tools for data processing, quality assessment, and identifying essential genes through rigorous statistical analysis.