A5080724294- Tuberculosis Research and Epidemiology
- Biochemical and Molecular Research
- Mycobacterium research and diagnosis
- Antibiotic Resistance in Bacteria
- Bacterial Genetics and Biotechnology
- Enzyme Structure and Function
- Metabolomics and Mass Spectrometry Studies
- Pneumocystis jirovecii pneumonia detection and treatment
- Cancer therapeutics and mechanisms
- RNA and protein synthesis mechanisms
- Diet, Metabolism, and Disease
- Neurological diseases and metabolism
- Antimicrobial Resistance in Staphylococcus
- Microbial Natural Products and Biosynthesis
- Vibrio bacteria research studies
- Metabolism, Diabetes, and Cancer
- Metabolism and Genetic Disorders
- Bacteriophages and microbial interactions
- Cancer, Hypoxia, and Metabolism
- Health and Medical Research Impacts
- Antibiotics Pharmacokinetics and Efficacy
- Porphyrin Metabolism and Disorders
- Diagnosis and treatment of tuberculosis
- Bacterial Identification and Susceptibility Testing
- Microbial Metabolism and Applications
Cornell University
2016-2025
Weill Cornell Medicine
2016-2025
Office of Infectious Diseases
2009-2025
University of Groningen
2024
Center for Global Health
2018-2020
New York Proton Center
2017
Children's Hospital Association
2013
Presbyterian Hospital
2009
New York Hospital Queens
2009
NewYork–Presbyterian Hospital
2009
Metabolic adaptation to the host niche is a defining feature of pathogenicity Mycobacterium tuberculosis (Mtb) . In vitro, Mtb able grow on variety carbon sources, but mounting evidence has implicated fatty acids as major source and energy for during infection. When bacterial metabolism primarily fueled by acids, biosynthesis sugars from intermediates tricarboxylic acid cycle essential growth. The role gluconeogenesis in pathogenesis however remains unaddressed. Phosphoenolpyruvate...
Excessive consumption of beverages sweetened with high-fructose corn syrup (HFCS) is associated obesity and an increased risk colorectal cancer. Whether HFCS contributes directly to tumorigenesis unclear. We investigated the effects daily oral administration in adenomatous polyposis coli (APC) mutant mice, which are predisposed develop intestinal tumors. The HFCS-treated mice showed a substantial increase tumor size grade absence metabolic syndrome. concentrations fructose glucose lumen...
Candidate antibacterials are usually identified on the basis of their in vitro activity. However, apparent inhibitory activity new leads can be misleading because most culture media do not reproduce an environment relevant to infection vivo. In this study, while screening for novel anti-tuberculars, we uncovered how carbon metabolism affect antimicrobial Novel pyrimidine-imidazoles (PIs) were a whole-cell screen against Mycobacterium tuberculosis. Lead optimization generated potent...
Mycobacterium tuberculosis is a chronic, facultative intracellular pathogen that spends the majority of its decades-long life cycle in non- or slowly replicating state. However, bacterium remains poised to resume so it can transmit itself new host. Knowledge metabolic adaptations used facilitate entry into and exit from nonreplicative states incomplete. Here, we apply 13 C-based metabolomic profiling characterize activity M. tricarboxylic acid during adaptation recovery hypoxia,...
Abstract Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of adenomas after oral delivery probiotic E. coli Nissle 1917 (EcN) a genetically-engineered murine model CRC predisposition orthotopic models CRC. We next undertake an interventional, double-blind, dual-centre, prospective clinical trial, in which patients take either placebo or EcN for two weeks prior resection...
Folate biosynthesis is an established anti-infective target, and the antifolate para-aminosalicylic acid (PAS) was one of first anti-infectives introduced into clinical practice on basis target-based drug discovery. Fifty years later, PAS continues to be used treat tuberculosis. assumed inhibit dihydropteroate synthase (DHPS) in Mycobacterium tuberculosis by mimicking substrate p-aminobenzoate (PABA). However, we found that sulfonamide inhibitors DHPS inhibited growth M. only weakly because...
It is often assumed that antibiotics act on the most vulnerable cellular targets, particularly those require limited inhibition to block growth. To evaluate this assumption, we developed a genetic method can inducibly deplete targeted proteins and mimics their chemical inactivation. We applied system current antibiotic targets in mycobacteria. Although depleting some significantly perturbs bacterial growth, surprisingly, found reducing levels of other by more than 97% had little or no effect...
Significance Essentiality is a phenotypic trait of genes frequently used to identify new potential drug targets. However, function within the context complex and extensively interconnected physiologic networks, making it difficult discern specific mechanisms responsible for their essentiality. Here, we apply combination chemogenetic metabolomic approaches resolve biochemical mechanism associated with bactericidal essentiality metabolic enzyme, isocitrate lyase (ICL), survival Mycobacterium...
Highlights•WhiB3 regulates EGT production and maintains bioenergetic homeostasis in Mtb•EGT modulates drug sensitivity protects Mtb from diverse oxidative stressors•EGT is essential for survival macrophages miceSummaryThe mechanisms by which Mycobacterium tuberculosis (Mtb) metabolic equilibrium to survive during infection upon exposure antimycobacterial drugs are poorly characterized. Ergothioneine (EGT) mycothiol (MSH) the major redox buffers present Mtb, but contribution of virulence...
Significance Chronic bacterial infections, such as those caused by Mycobacterium tuberculosis ( Mtb ), continue to claim the lives of millions people. New antibiotics are needed treat these but their development is hindered a lack targets whose inhibition quickly eradicates pathogens and prevents survival drug-tolerant persisters. We describe unique dual-control (DUC) switch that combines repression transcription controlled proteolysis silence gene activities in . By conditionally...
In the search for new drug targets, we evaluated biotin synthetic pathway of Mycobacterium tuberculosis (Mtb) and constructed an Mtb mutant lacking biosynthetic enzyme 7,8-diaminopelargonic acid synthase, BioA. biotin-free media, ΔbioA did not produce wild-type levels biotinylated proteins, therefore grow lost viability. was also unable to establish infection in mice. Conditionally-regulated knockdown strains similarly exhibited impaired bacterial growth viability vitro mice, irrespective...
Mycobacterium tuberculosis kills more people than any other bacterial pathogen and is becoming increasingly untreatable due to the emergence of resistance. Verapamil, an FDA-approved calcium channel blocker, potentiates effect several antituberculosis (anti-TB) drugs in vitro vivo This potentiation widely attributed inhibition efflux pumps M. tuberculosis, resulting intrabacterial drug accumulation. Here, we confirmed quantified verapamil's synergy with anti-TB drugs, including bedaquiline...
Significance This report reveals that the more than 200 genes controlled by Bacillus subtilis global regulatory protein CodY are in a hierarchical manner reflects extent of activation its ligands. The results suggest B. uses regulation to achieve strategic goals.
Significance A better understanding of essential processes in Mycobacterium tuberculosis ( Mtb ) is required for the development new chemotherapeutics. Isocitrate lyase (ICL) and malate synthase (MS) function glyoxylate shunt, a pathway by to metabolize fatty acids (FAs). Here, we demonstrate that MS enables growth survival on through its ability simultaneously detoxify metabolic byproduct arising from initial assimilation acetyl coenzyme (acetyl-CoA), glyoxylate, while assimilating second...
Significance Better understanding of the mechanisms used by bacteria to counter antibacterial agents is essential cope with rising prevalence antimicrobial resistance. Here, we identified mechanism resistance Mycobacterium tuberculosis an antimycobacterial cyano-substituted fused pyrido-benzimidazole. Clones bearing mutations in a transcription factor, Rv2887, markedly up-regulated expression rv0560c , putative methyltransferase. Rv0560c N -methylated pyrido-benzimidazole vitro and...
Respiration is a promising target for the development of new antimycobacterial agents, with growing number compounds in clinical entering this space. However, more candidate inhibitors are needed to expand therapeutic options available drug-resistant Mycobacterium tuberculosis infection. Here, we characterize putative respiratory complex III (QcrB) inhibitor, TB47: pyrazolo[1,5-a]pyridine-3-carboxamide. TB47 active (MIC between 0.016 and 0.500 μg/mL) against panel 56 M. isolates, including...