A5063086157- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Bacteriophages and microbial interactions
- Innovative Microfluidic and Catalytic Techniques Innovation
- Parasites and Host Interactions
- Parasite Biology and Host Interactions
- Trace Elements in Health
- Antibiotic Resistance in Bacteria
- Inhalation and Respiratory Drug Delivery
- 3D Printing in Biomedical Research
- SARS-CoV-2 and COVID-19 Research
- Cancer therapeutics and mechanisms
- Cystic Fibrosis Research Advances
- SARS-CoV-2 detection and testing
- Peptidase Inhibition and Analysis
- Helminth infection and control
- Magnesium in Health and Disease
- Research on Leishmaniasis Studies
- Heat shock proteins research
- Escherichia coli research studies
- Pneumocystis jirovecii pneumonia detection and treatment
- Infectious Diseases and Tuberculosis
- Yersinia bacterium, plague, ectoparasites research
- Asthma and respiratory diseases
- Pneumonia and Respiratory Infections
Weill Cornell Medicine
2019-2025
Cornell University
2015-2025
Draper Laboratory
2022-2024
University of California, San Francisco
2011-2012
Abstract Mycobacterium tuberculosis (Mtb), a leading cause of death from infection, completes its life cycle entirely in humans except for transmission through the air. To begin to understand how Mtb survives aerosolization, we mimicked liquid and atmospheric conditions experienced by before after exhalation using model aerosol fluid (MAF) based on water-soluble, lipidic cellular constituents necrotic lesions. MAF induced drug tolerance Mtb, remodeled transcriptome protected dying...
Mycobacterium tuberculosis (Mtb), a leading cause of death from infection, completes its life cycle entirely in humans except for transmission through the air. To begin to understand how Mtb survives aerosolization, we mimicked liquid and atmospheric conditions experienced by before after exhalation using model aerosol fluid (MAF) based on water-soluble, lipidic, cellular constituents necrotic lesions. MAF induced drug tolerance Mtb, remodeled transcriptome, protected dying microdroplets...
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...
Serpins are a structurally conserved family of macromolecular inhibitors found in numerous biological systems. The completion and annotation the genomes Schistosoma mansoni japonicum has enabled identification by phylogenetic analysis two major serpin clades. S. shows greater multiplicity genes, perhaps reflecting adaptation to infection human host. Putative targets schistosome serpins can be predicted from sequence reactive center loop (RCL). Schistosome may play important roles both...
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...
COVID-19 emerged as a worldwide pandemic in early 2020, and while the rapid development of safe efficacious vaccines stands an extraordinary achievement, identification effective therapeutics has been less successful. This process limited part by lack human-relevant preclinical models compatible with therapeutic screening on native virus, which requires high-containment environment. Here, we report SARS-CoV-2 infection robust viral replication PREDICT96-ALI, high-throughput, human primary...
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...
There is an urgent need to discover and progress anti-infectives that shorten the duration of tuberculosis (TB) treatment. Mycobacterium tuberculosis, etiological agent TB, refractory rapid lasting chemotherapy due presence bacilli exhibiting phenotypic drug resistance. The charcoal agar resazurin assay (CARA) was developed as a tool characterize active molecules discovered by high-throughput screening campaigns against replicating non-replicating M. tuberculosis. Inclusion activated in...
Abstract Despite the relatively common observation of therapeutic efficacy in discovery screens with immortalized cell lines, vast majority drug candidates do not reach clinical development. Candidates that move forward often fail to demonstrate when progressed from animal models humans. This dilemma highlights need for new screening technologies can parse early development regard predicted relevance use. PREDICT96-ALI is a high-throughput organ-on-chip platform incorporating human primary...
Abstract The average cost to bring a new drug from its initial discovery patient's bedside is estimated surpass $2 billion and requires over decade of research development. There need for screening technologies that can parse candidates with increased likelihood clinical utility early in development order increase the cost‐effectiveness this pipeline. For example, during COVID‐19 pandemic, resources were rapidly mobilized identify effective therapeutic treatments but many lead antiviral...
Abstract The COVID-19 pandemic necessitated a rapid mobilization of resources toward the development safe and efficacious vaccines therapeutics. Finding effective treatments to stem wave infected individuals needing hospitalization reduce risk adverse events was paramount. For scientists healthcare professionals addressing this challenge, need rapidly identify medical countermeasures became urgent, many compounds in clinical use for other indications were repurposed trials after preliminary...