A5003127274- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Synthesis and biological activity
- Immunotherapy and Immune Responses
- SARS-CoV-2 and COVID-19 Research
- Immune cells in cancer
- Pneumocystis jirovecii pneumonia detection and treatment
- Immune Cell Function and Interaction
- Diagnosis and treatment of tuberculosis
- Chemokine receptors and signaling
- Immune responses and vaccinations
- Synthesis of Tetrazole Derivatives
- Hydrogels: synthesis, properties, applications
- Inflammation biomarkers and pathways
- Antimicrobial Peptides and Activities
- RNA and protein synthesis mechanisms
- RNA Interference and Gene Delivery
- Biochemical and Molecular Research
- 3D Printing in Biomedical Research
- Cytokine Signaling Pathways and Interactions
- Cancer therapeutics and mechanisms
- COVID-19 Clinical Research Studies
- Bacteriophages and microbial interactions
- Tissue Engineering and Regenerative Medicine
- Phenothiazines and Benzothiazines Synthesis and Activities
The University of Texas Medical Branch at Galveston
2019-2024
University of Washington
2023-2024
Infectious Disease Research Institute
2014-2022
Galveston College
2022
Kineta (United States)
2018
Arenaviruses are a significant cause of hemorrhagic fever, an often-fatal disease for which there is no approved antiviral therapy. Lassa fever in particular generates high morbidity and mortality West Africa, where the endemic, recent outbreak Nigeria was larger more geographically diverse than usual. We developing LHF-535, small-molecule viral entry inhibitor that targets arenavirus envelope glycoprotein, as therapeutic candidate other fevers origin. Using lentiviral pseudotype infectivity...
We conducted an evaluation of the phenoxyalkylbenzimidazole series based on exemplar 2-ethyl-1-(3-phenoxypropyl)-1H-benzo[d]imidazole for its antitubercular activity. Four segments molecule were examined systematically to define a structure-activity relationship with respect biological Compounds had submicromolar activity against Mycobacterium tuberculosis; most potent compound minimum inhibitory concentration (MIC) 52 nM and was not cytotoxic eukaryotic cells (selectivity index = 523)....
Mycobacterium tuberculosis is a global pathogen of huge importance which can adapt to several host niche environments in carbon source availability likely vary. We developed and ran phenotypic screen using butyrate as the sole be more reflective lung environment. screened library ∼87,000 small compounds identified demonstrated good antitubercular activity against M. grown with but not glucose source. Among hits, we an oxadiazole series (six compounds) had specific lacked cytotoxicity mammalian cells.
The general secretion (Sec) pathway is a conserved essential in bacteria and the primary route of protein export across cytoplasmic membrane. During export, signal peptidase LepB catalyzes cleavage peptide subsequent release mature proteins into extracellular space. We developed target-based whole cell assay to screen for potential inhibitors LepB, sole Mycobacterium tuberculosis, using strain engineered underexpress (LepB-UE). screened 72,000 compounds against both Lep-UE wild-type (wt)...
There is an urgent need for the development of shorter, simpler and more tolerable drugs to treat antibiotic tolerant populations Mycobacterium tuberculosis. We previously identified a series hydrazones active against M. selected five representative compounds further analysis. All were non-replicating tuberculosis, with two demonstrating greater activity under hypoxic conditions than aerobic culture. Compounds had bactericidal MBC/MIC < 4 demonstrated inoculum-dependent effect aerobically...
Abstract Heterologous vaccine regimens could extend waning protection in the global population immunized with Mycobacterium bovis Bacille Calmette-Guerin (BCG). We demonstrate that pulmonary delivery of peptide nanofibers (PNFs) bearing an Ag85B CD4 + T cell epitope increased frequency antigen-specific cells BCG-primed mice, including heterogenous populations tissue resident memory (Trm) and effector (Tem) phenotype, functional cytokine recall. Adoptive transfer dendritic pulsed...
Nitazoxanide has antiparasitic and antibiotic activities including activity against Mycobacterium tuberculosis. We prepared evaluated a set of its analogues to determine the structure–activity relationship, identified several amide- urea-based with low micromolar M. tuberculosis in vitro. Pharmacokinetics rat suggested path forward obtain bioavailable compounds. The series had good microbiological profile bactericidal vitro replicating nonreplicating Analogues limited other Gram-positive...
ABSTRACT There is an urgent need for new treatments effective against Mycobacterium tuberculosis , the causative agent of tuberculosis. The 8‐hydroxyquinoline series a privileged scaffold with anticancer, antifungal, and antibacterial activities. We conducted structure–activity relationship study regarding its antitubercular activity using 26 analogs. 8‐hydroxyquinolines showed good M. tuberculosis, minimum inhibitory concentrations (MIC90) <5 μM some Small substitutions at C5 resulted in...
Alginate hydrogels are widely used for tissue engineering and regenerative medicine due to their excellent biocompatibility. A facile commonly strategy crosslink alginate is the addition of Ca2+ that leads hydrogelation. However, extracellular a secondary messenger in activating inflammasome pathways following physical injury or pathogenic insult, which carries risk persistent inflammation scaffold rejection. Here, we present graft copolymers charge complementary heterodimeric coiled coil...
We demonstrated that the 3-substituted benzothiophene-1,1-dioxide class of compounds are effective inhibitors Mycobacterium tuberculosis growth under aerobic conditions. examined substitution at C-3 position series systematically to delineate structure–activity relationships influencing potency and cytotoxicity. Compounds were tested for inhibitory activity against virulent M. eukaryotic cells. The tetrazole substituent was most potent, with a minimum concentration (MIC) 2.6 µM. However,...
This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors Mycobacterium tuberculosis (Mtb) proteasome. As part study, structure-activity relationship oxathiazolones Mtb proteasome has been investigated. Furthermore, prepared compounds displayed a good selectivity profile for compared to human The 5-styryl-oxathiazol-2-one identified showed little activity against replicating Mtb, but were rapidly bactericidal nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one)...
Fluorescent proteins are used widely as reporter genes in many organisms. We previously codon-optimized mCherry for Mycobacterium tuberculosis and generated expression constructs with high level mycobacteria multiple uses vitro vivo. However, little is known about the of fluorescent translational start codon has not been experimentally determined. determined site functional (fluorescent) mycobacteria. Several potential codons were identified; introduction downstream stop by mutagenesis was...
There is a pressing need to develop novel anti-tubercular drugs. High-throughput phenotypic screening yields chemical series that inhibit bacterial growth. Target identification for such challenging, but necessary optimization of target engagement and the development into clinical We constructed library recombinant Mycobacterium tuberculosis strains each expressing single protein from an inducible promoter as tool identification. The 1733 clones was arrayed in 96-well plates rapid monitoring...
We performed a high-throughput phenotypic whole cell screen of Mycobacterium tuberculosis against diverse chemical library approximately 100,000 compounds from the AbbVie corporate collection and identified 24 chemotypes with anti-tubercular activity. selected two series for further exploration conducted structure-activity relationship studies new analogs 4-phenyl piperidines (4PP) phenylcyclobutane carboxamides (PCB). Strains mutations in MmpL3 demonstrated resistance to both compound...
Abstract There is an urgent need for the development of shorter, simpler and more tolerable drugs to treat antibiotic tolerant populations Mycobacterium tuberculosis . We previously identified a series phenylhydrazones (PHY) active against M. selected six representative compounds further analysis. All were non-replicating , with two demonstrating greater activity under hypoxic conditions than aerobic culture. Compounds had bactericidal MBC/MIC <4 demonstrated inoculum-dependent effect...
Abstract Background The kinetics and durability of T-cell responses to SARS-CoV-2 in children are not well characterized. We studied a cohort aged 6 months 20 years with COVID-19 whom peripheral blood mononuclear cells sera were archived at approximately 1, 6, 12 after symptom onset. Methods compared antibody (n = 85) 30) nucleocapsid (N) spike (S) glycoprotein over time across 4 age strata: 5 5–9, 10–14, 15–20 years. Results N-specific declined time, becoming undetectable 26 (81%) 32 by 1...
ABSTRACT Vaccine adjuvants are typically composed of pathogen-associated molecular patterns (PAMPs) or danger-associated (DAMPs) that activate innate immune cells. Advances in basic immunology have demonstrated the need for various ‘types’ protective immunity, which difficult to achieve with a single adjuvant. The FDA approval multiple PAMP-DAMP combinations clinical use has led an increased momentum area recent years. Here we report DAMP-inducing peptide nanofibers (PNFs) and CL429 (PAMP)...
Abstract Tuberculosis (TB) infection caused by Mycobacterium tuberculosis (Mtb) is a serious threat to global health with 10 million new infections each year and 1–2 deaths. The only licensed vaccine approved for human use, bovis Bacille Calmette-Guerin (BCG), has been administered 4 billion people despite variable efficacy. Heterologous regimens that boost T cell memory generated through BCG priming, however, may be an effective immunization strategy. Our lab previously demonstrated...
Abstract Mycobacterium tuberculosis (Mtb), the causative agent of (TB), is responsible for approximately 10 million new infections and 1.5 deaths each year. Pattern recognition receptors (PRRs) expressed on surface macrophages play an important role in orchestrating immune response to pathogens. Amongst these, C-type lectin (CLRs) are PRR system that increasingly understood mediate innate immunity mycobacteria. We recently described a anti-bacterial anti-inflammatory macrophage...
Currently approved replication-competent and inactivated vaccines are limited by excessive reactogenicity poor safety profiles, while subunit often insufficiently immunogenic without exogenous adjuvants. Self-assembling peptide-, peptidomimetic-, protein-based biomaterials offer a means to overcome these challenges through their inherent modularity, multivalency, biocompatibility. As scaffolds biologically derived present antigenic arrays reminiscent of natural viruses, they prone immune...