A5023809479- Mycobacterium research and diagnosis
- Tuberculosis Research and Epidemiology
- Bacteriophages and microbial interactions
- Bacterial Genetics and Biotechnology
- Antibiotic Resistance in Bacteria
- Biosensors and Analytical Detection
- SARS-CoV-2 detection and testing
- RNA and protein synthesis mechanisms
- Genomics and Phylogenetic Studies
- SARS-CoV-2 and COVID-19 Research
- vaccines and immunoinformatics approaches
- Biosimilars and Bioanalytical Methods
- Infectious Diseases and Mycology
- Actinomycetales infections and treatment
- Computational Drug Discovery Methods
- Cell Image Analysis Techniques
- Infections and bacterial resistance
- ATP Synthase and ATPases Research
- Biochemical and Molecular Research
- Peptidase Inhibition and Analysis
- CRISPR and Genetic Engineering
- Protein Degradation and Inhibitors
- Protein Structure and Dynamics
Harvard University
2019-2025
Proteolysis-targeting chimeras (PROTACs) represent a new therapeutic modality involving selectively directing disease-causing proteins for degradation through proteolytic systems. Our ability to exploit targeted protein (TPD) antibiotic development remains nascent due our limited understanding of which bacterial are amenable TPD strategy. Here, we use genetic system model chemically-induced proximity and screen essential in Mycobacterium smegmatis (Msm), the human pathogen M. tuberculosis...
Mycobacterium abscessus ( Mab ) is a rapidly growing non-tuberculous mycobacterium (NTM) that causes wide range of infections. Treatment infections difficult because the bacterium intrinsically resistant to many classes antibiotics. Developing new and effective treatments against requires better understanding unique vulnerabilities can be targeted for future drug development. To achieve this, we identified essential genes in by conducting transposon sequencing (TnSeq) on reference strain...
MtbClpC1 is a promising drug target against tuberculosis. Recent studies have shown that several natural product antibiotics targeting the unfoldase N-terminal domain can impair function resulting in cell death. While pharmacological properties of these prevent their use clinic, similar molecules binding to same pockets result new drugs Mtb. Here we demonstrate successfully used silico screening identify ClpC1 binders with micromolar affinity from small compound library. In addition,...
Mycobacterium abscessus is a pulmonary pathogen that exhibits intrinsic resistance to antibiotics, but the factors driving this are incompletely understood. Insufficient intracellular drug accumulation could explain broad-spectrum resistance, whether antibiotics fail accumulate in M. and mechanisms required for exclusion remain poorly We measured antibiotic using mass spectrometry found wide range of across clinically relevant antibiotics. Of these compounds, linezolid accumulates least,...
Functional characterization of bacterial proteins lags far behind the identification new protein families. This is especially true for species that are more difficult to grow and genetically manipulate than model systems such as
Although prokaryotic organisms lack traditional organelles, they must still organize cellular structures in space and time, challenges that different species solve differently. To systematically define the subcellular architecture of mycobacteria, we perform high-throughput imaging a library fluorescently tagged proteins expressed Mycobacterium smegmatis develop customized computational pipeline, MOMIA GEMATRIA, to analyze these data. Our results establish spatial organization network over...
is a pulmonary pathogen that exhibits intrinsic resistance to antibiotics, but the factors driving this are incompletely understood. Insufficient intracellular drug accumulation could explain broad-spectrum resistance, whether antibiotics fail accumulate in
Genomic dissection of antibiotic resistance in bacterial pathogens has largely focused on genetic changes conferring growth above a single critical concentration drug. However, reduced susceptibility to antibiotics—even below this breakpoint—is associated with poor treatment outcomes the clinic, including tuberculosis. Clinical strains Mycobacterium tuberculosis exhibit extensive quantitative variation but basis behind spectrum drug remains ill-defined. Through genome wide association study,...
Nontuberculous mycobacteria are water-avid pathogens that associated with nosocomial infections. To describe the analysis and mitigation of a cluster Mycobacterium abscessus infections in cardiac surgery patients. Descriptive study. Brigham Women's Hospital, Boston, Massachusetts. Four Commonalities among cases were sought, potential sources cultured, patient environmental specimens sequenced, possible abated. Description cluster, investigation, mitigation. Whole-genome sequencing confirmed...
Abstract There has been debate in the literature about ability of antigen tests to detect SARS-CoV-2 Omicron variant including indication on US Food and Drug administration website that may have lower sensitivity for without provision data or potential scale issue (see https://www.fda.gov/medical-devices/coronavirus-covid-19-and-medical-devices/sars-cov-2-viral-mutations-impact-covid-19-tests-omicronvariantimpact , accessed 1/27/2022). Here we determined limit detection (LoD) compared with...
The mycobacterial cell wall is a promising target for new antibiotics due to the abundance of important membrane-associated proteins. Defining mechanisms synthesis membrane proteome will be critical uncovering and validating drug targets.
Abstract Mycobacterium abscessus ( Mab ) is a rapidly growing non-tuberculous mycobacterium (NTM) that causes wide range of infections. Treatment infections difficult because the bacterium intrinsically resistant to many classes antibiotics. Developing new and effective treatments against requires better understanding unique vulnerabilities can be targeted for future drug development. To achieve this, we identified essential genes in by conducting transposon-sequencing (TnSeq) on reference...
) is a clinically significant pathogen and highly genetically diverse species due to its large accessory genome. The functional consequence of this diversity remains unknown mainly because, date, genomic studies in
Abstract Proteolysis-targeting chimeras (PROTACs) represent a new therapeutic modality involving selectively directing disease-causing proteins for degradation through proteolytic systems. Our ability to exploit this targeted protein (TPD) approach antibiotic development remains nascent due our limited understanding of which bacterial will be labile TPD targets. Here, we use genetic system model chemically-induced proximity and screen essential in Mycobacterium smegmatis ( Msm ), the major...
Abstract Mycobacterium abscessus is an emerging pathogen resistant to most frontline antibiotics. M. causes lung infection, predominantly in patients with disease or structural abnormalities. To interrogate mechanisms required for survival the lung, we developed a infection model using air-liquid interface culture and performed screen identify differentially genes. In model, synthesis of cofactor biotin due increased intracellular demand, pharmacological inhibition halts proliferation....
Abstract Ribosomes require the activity of associated GTPases to synthesize proteins. Despite strong evolutionary conservation, roles many these remain unknown. For example, LepA (also known as elongation factor 4) is a ribosome-associated GTPase found in bacteria, mitochondria, and chloroplasts, yet its physiological contribution cell survival not clear. Recently, we that loss lepA Mycobacterium smegmatis (Msm) altered tolerance rifampin, drug targets non-ribosomal cellular process. To...