A5059011773- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Biochemical and Molecular Research
- Antibiotic Resistance in Bacteria
- Dialysis and Renal Disease Management
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Phenothiazines and Benzothiazines Synthesis and Activities
- Pneumocystis jirovecii pneumonia detection and treatment
- COVID-19 Clinical Research Studies
- HIV/AIDS drug development and treatment
- Trace Elements in Health
- Cancer therapeutics and mechanisms
- Infectious Diseases and Tuberculosis
- SARS-CoV-2 and COVID-19 Research
- Immune Response and Inflammation
- Neurological diseases and metabolism
- Synthesis and Reactivity of Heterocycles
- Bacteriophages and microbial interactions
- Sarcoidosis and Beryllium Toxicity Research
- Synthesis of β-Lactam Compounds
- Diet and metabolism studies
- Inflammatory Bowel Disease
- Heat shock proteins research
- Peptidase Inhibition and Analysis
- Synthesis and Catalytic Reactions
Cornell University
2015-2024
Weill Cornell Medicine
2016-2024
Ysbyty Gwynedd Hospital NHS Trust
2022
NYU Langone Health
2017
RELX Group (United States)
2017
Illinois College
2017
Polycystic Kidney Disease Foundation
2017
New York University
2005
Mycobacterium tuberculosis can persist in macrophage phagosomes that acidify to a pH of approximately 4.5 after activation the with gamma interferon. How bacterium resists low acidified phagosome is incompletely understood. A screen 10,100 M. transposon mutants for hypersensitive led discovery 21 genes whose disruption attenuated survival at (41). Here, we show acid-sensitive insertions Rv2136c, Rv2224c, ponA2, and lysX were antibiotics, sodium dodecyl sulfate, heat shock, reactive oxygen...
Mycobacterium tuberculosis (Mtb) encounters stresses during the pathogenesis and treatment of (TB) that can suppress replication bacteria render them phenotypically tolerant to most available drugs. Where studied, majority Mtb in sputum untreated subjects with active TB have been found be nonreplicating by criterion they do not grow as colony-forming units (cfus) when plated on agar. However, these cells are viable because diluted liquid media. A method for generating such "differentially...
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...
Existing drugs are slow to eradicate Mycobacterium tuberculosis (Mtb) in patients and have failed control globally. One reason may be that host conditions impair Mtb’s replication, reducing its sensitivity most antiinfectives. We devised a high-throughput screen for compounds kill Mtb when replication has been halted by reactive nitrogen intermediates (RNIs), acid, hypoxia, fatty acid carbon source. At concentrations routinely achieved human blood, oxyphenbutazone (OPB), an inexpensive...
It is urgent to introduce new drugs for tuberculosis shorten the prolonged course of treatment and control drug-resistant Mycobacterium (Mtb). One strategy toward this goal develop antibiotics that eradicate both replicating (R) nonreplicating (NR) Mtb. Naturally occurring (+)-calanolide A was active against R-Mtb. The present report details design, synthesis, antimycobacterial activities, structure-activity relationships synthetic calanolides. We identified potent dual-active...
Observational studies have suggested a relationship between the plasma concentration of indoxyl sulfate (IS) and p-cresyl (PCS), small gut-derived 'uremic solutes', high incidence uremic cardiomyopathy in patients with end-stage renal disease (ESRD). IS PCS are derived from metabolism dietary components (tryptophan tyrosine) by gut bacteria. This pilot study was designed to examine effects poorly absorbable antibiotic (vancomycin) on two PCS, composition microbiome.Plasma concentrations were...
Rare kidney diseases encompass at least 150 different conditions, most of which are inherited. Although individual rare raise specific issues, as a group these can have overlapping challenges in diagnosis and treatment. These include small numbers affected patients, unidentified causes disease, lack biomarkers for monitoring disease progression, need complex care. To address common clinical patient issues among diseases, the KDIGO Controversies Conference entitled, Common Elements Kidney...
Mycobacterium tuberculosis that sustains moderate oxidative damage survives undetected on solid media, but growth delay restores replicative ability.
We report two series of novel cephalosporins that are bactericidal to Mycobacterium tuberculosis alone the pathogens tested, which only kill M. when its replication is halted by conditions resembling those believed pertain in host, and whose activity not dependent upon or enhanced clavulanate, a β-lactamase inhibitor. The classes bear an ester alternatively oxadiazole isostere at C-2 cephalosporin ring system, position almost exclusively carboxylic acid clinically used agents class....
Identification of compounds that target metabolically diverse subpopulations Mycobacterium tuberculosis (Mtb) may contribute to shortening the course treatment for tuberculosis. This study screened 270,000 from GlaxoSmithKline's collection against Mtb in a nonreplicating (NR) state imposed vitro by combination four host-relevant stresses. Evaluation 166 confirmed hits led detailed characterization 19 potency, specificity, cytotoxicity, and stability. Compounds representing five scaffolds...
Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework multiple pharmaceutical companies share proprietary information and compounds with laboratories in academic government sectors broad examination β-lactams kill Mycobacterium (Mtb). In TB Drug Accelerator (TBDA), consortium organized by Bill & Melinda Gates Foundation,...
Through chemical screening, we identified a pyrazolone that reversibly blocked the activation of phagocyte oxidase (phox) in human neutrophils response to tumor necrosis factor (TNF) or formylated peptide. The spared phox by phorbol ester bacteria, bacterial killing, TNF-induced granule exocytosis and assembly, endothelial transmigration. We traced pyrazolone's mechanism action inhibition intracellular Ca2+ elevations, nontransmembrane (“soluble”) adenylyl cyclase (sAC) as Ca2+-sensing...
The search for drugs that can kill replicating and nonreplicating Mycobacterium tuberculosis faces practical bottlenecks. Measurement of CFU discrimination bacteriostatic from bactericidal activity are costly in compounds, supplies, labor, time. Testing compounds against M. under conditions prevent the replication often involves a second phase test which altered to permit bacteria survived first phase. False-positive determinations may arise carryover stage assay act stage. We mitigate these...
A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors Mycobacterium tuberculosis. The structure-activity relationships recently disclosed inhibitor, amidinourea (AU) 8918 (1), were explored, focusing on biochemical potency, determination whole-cell on-target activity active compounds, profiling selective congeners. These studies show AU moiety largely...
In spite of its highly immunogenic properties, Mycobacterium tuberculosis (Mtb) establishes persistent infection in otherwise healthy individuals, making it one the most widespread and deadly human pathogens. Mtb's prolonged survival may reflect production microbial factors that prevent even more vigorous immunity (quantitative effect) or divert immune response to a non-sterilizing mode (qualitative effect). Disruption Mtb genes has produced list several dozen candidate immunomodulatory...
Abstract Bacterial chaperones ClpB and DnaK, homologs of the respective eukaryotic heat shock proteins Hsp104 Hsp70, are essential in reactivation toxic protein aggregates that occur during translation or periods stress. In pathogen Mycobacterium tuberculosis (Mtb), protective effect extends to survival presence host stresses, such as protein‐damaging oxidants. However, we lack a full understanding interplay Hsps other stress response genes mycobacteria. Here, employ genome‐wide transposon...
The success of Mycobacterium tuberculosis (Mtb) as a pathogen depends on the redundant and complex mechanisms it has evolved for resisting nitrosative oxidative stresses inflicted by host immunity. Improving our understanding these defense pathways can reveal vulnerable points in Mtb pathogenesis. In this study, we combined genetic, structural, computational, biochemical, biophysical approaches to identify novel enzyme class represented Rv2466c. We show that Rv2466c is mycothiol-dependent...
As -lactams are reconsidered for the treatment of tuberculosis (TB), their targets assumed to be peptidoglycan transpeptidases, as verified by adduct formation and kinetic inhibition Mycobacterium (Mtb) transpeptidases carbapenems active against replicating Mtb. Here we investigated recently described cephalosporins that selectively nonreplicating (NR) NR-active failed inhibit recombinant Mtb transpeptidases. Accordingly, used alkyne analogs pull down potential through unbiased...
A defining characteristic of treating tuberculosis is the need for prolonged administration multiple drugs. This may be due in part to subpopulations slowly replicating or nonreplicating Mycobacterium bacilli exhibiting phenotypic tolerance most antibiotics standard treatment regimen. Confounding this problem increasing incidence heritable multidrug-resistant M. search new antimycobacterial chemical scaffolds that can kill phenotypically drug-tolerant mycobacteria uncovered tricyclic...
The historical view of β-lactams as ineffective antimycobacterials has given way to growing interest in the activity this class against Mycobacterium tuberculosis (Mtb) presence a β-lactamase inhibitor. However, most antimycobacterial kill Mtb only or best when bacilli are replicating. Here, screen 1904 led identification cephalosporins substituted with pyrithione moiety at C3′ that active under both replicating and nonreplicating conditions, neither requiring Studies showed required situ...
4′-Phosphopantetheinyl transferase (PptT) is an essential enzyme for Mycobacterium tuberculosis (Mtb) survival and virulence therefore attractive target a therapeutic. In this work, two modeling-informed approaches toward the isosteric replacement of amidinourea moiety present in previously reported PptT inhibitor AU 8918 are reported. Although designed 3,5-diamino imidazole unexpectedly adopted undesired tautomeric form was inactive, afforded series active inhibitors containing...
There is a compelling need to find drugs active against Mycobacterium tuberculosis ( Mtb ). 4′-Phosphopantetheinyl transferase (PptT) an essential enzyme in that has attracted interest as potential drug target. We optimized PptT assay, used it screen 422,740 compounds, and identified raltitrexed, antineoplastic antimetabolite, the most potent inhibitor yet reported. While trying unsuccessfully improve raltitrexed’s ability kill remove its human cells, we learned three lessons may help others...
Goodpasture's syndrome (GPS) remains a very rare disease entity in the pediatric population characterized by presence of pulmonary hemorrhage and rapidly evolving glomerulonephritis. We hereby describe case 2-year-old girl who presented with renal failure was diagnosed GPS. A brief review literature regard to data on demographics, pathogenesis, clinical features, diagnosis, treatment, prognosis for recovery is also provided.