A5066023246- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Antibiotic Resistance in Bacteria
- Cancer therapeutics and mechanisms
- Biochemical and Molecular Research
- Computational Drug Discovery Methods
- Diagnosis and treatment of tuberculosis
- Antibiotics Pharmacokinetics and Efficacy
- Pneumonia and Respiratory Infections
- Pneumocystis jirovecii pneumonia detection and treatment
- Biosimilars and Bioanalytical Methods
- Pharmacological Effects of Natural Compounds
- Fungal Infections and Studies
- Infectious Diseases and Tuberculosis
- Bioactive Compounds and Antitumor Agents
- Plant-Microbe Interactions and Immunity
- Infectious Diseases and Mycology
- Antifungal resistance and susceptibility
- Drug Solubulity and Delivery Systems
- HIV/AIDS drug development and treatment
- Radiopharmaceutical Chemistry and Applications
- Medical Imaging Techniques and Applications
- Drug Transport and Resistance Mechanisms
- ATP Synthase and ATPases Research
- Clostridium difficile and Clostridium perfringens research
Hackensack Meridian Health
2020-2025
Center for Discovery
2020-2025
Hackensack University Medical Center
2022
Seton Hall University
2020
Rutgers, The State University of New Jersey
2015-2019
Rutgers New Jersey Medical School
2016-2017
Novartis (Singapore)
2012-2013
ABSTRACT Tuberculosis (TB) recently became the leading infectious cause of death in adults, while attempts to shorten therapy have largely failed. Dormancy, persistence, and drug tolerance are among factors driving long duration. Assays measure situ susceptibility Mycobacterium tuberculosis bacteria pulmonary lesions needed if we discover new fast-acting regimens address global TB threat. Here take a first step toward this goal describe an ex vivo assay developed cidal activity anti-TB drugs...
During active tuberculosis a spectrum of physiologically different Mycobacterium bacilli reside in human tissues. Subpopulations the pathogen survive antibiotic treatment for prolonged time dormant state phenotypic drug resistance, phenomenon independent genetic mutations. Here, we used an established culture model nutrient deprivation to shift down M. from growth nonreplicating survival, which is characterized by drastic loss susceptibility. Liquid chromatography coupled with mass...
The penetration of antibiotics in necrotic tuberculosis lesions is heterogeneous and drug-specific, but the factors underlying such differential partitioning are unknown. We hypothesized that drug binding to macromolecules foci (or caseum) prevents passive diffusion through avascular caseum, a critical site infection. Using caseum assay MALDI mass spectrometry imaging drugs, we showed inversely correlates with into core. developed high-throughput relying on rapid equilibrium dialysis...
In the fight against tuberculosis, cell wall permeation of chemotherapeutic agents remains a critical but largely unsolved question. Here we review major mechanisms small molecule penetration into and efflux from Mycobacterium tuberculosis other mycobacteria, outline how these may contribute to development phenotypic drug tolerance induction resistance. M. is intrinsically recalcitrant thanks its thick lipid-rich wall. Passive diffusion appears account for only fraction total permeation. As...
Abstract Candida glabrata is a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive proliferate within macrophages. Resembling bacterial persisters, subset genetically drug-susceptible C. cells can lethal exposure the fungicidal echinocandin drugs. Herein, we show that macrophage internalization induces cidal drug tolerance in , expanding persister reservoir from which echinocandin-resistant mutants emerge....
Pyrazinamide (PZA) is a critical component of first- and second-line treatments tuberculosis (TB), yet its mechanism action largely remains an enigma. We carried out genetic screen to isolate Mycobacterium bovis BCG mutants resistant pyrazinoic acid (POA), the bioactive derivative PZA, followed by whole genome sequencing 26 POA strains. Rather than finding mutations in proposed candidate targets fatty synthase I ribosomal protein S1, we found resistance conferring two pathways: missense...
Clinical trials and practice have shown that ethambutol is an important component of the first-line tuberculosis (TB) regime. This contrasts drug's rather modest potency lack activity against nongrowing persister mycobacteria. The standard plasma-based pharmacokinetic-pharmacodynamic profile suggests drug may be limited clinical value. Here, we hypothesized this apparent contradiction explained by favorable penetration into TB lesions. First, utilized novel in vitro lesion pharmacokinetic...
Granulomas are complex lung lesions that the hallmark of tuberculosis (TB). Understanding antibiotic dynamics within granulomas will be vital to improving and shortening long course TB treatment. Three fluoroquinolones (FQs) commonly prescribed as part multi-drug resistant therapy: moxifloxacin (MXF), levofloxacin (LVX) or gatifloxacin (GFX). To date, insufficient data available support selection one FQ over another, show these drugs clinically equivalent. predict efficacy MXF, LVX GFX at a...
Previously, we showed that a major in vitro and vivo mechanism of resistance to pyrazinoic acid (POA), the bioactive component critical tuberculosis (TB) prodrug pyrazinamide (PZA), involves missense mutations aspartate decarboxylase PanD, an enzyme required for coenzyme A biosynthesis. What is action POA? Upon demonstrating treatment M. bovis BCG with POA resulted depletion intracellular confirming this POA-mediated prevented by either PanD or exogenous supplementation pantothenate,...
The ability of Mycobacterium tuberculosis (Mtb) to resist and tolerate antibiotics complicates the development improved (TB) chemotherapies. Here we define Mtb protein CinA as a major determinant drug tolerance potential target shorten TB chemotherapy. By reducing fraction drug-tolerant persisters, genetic inactivation cinA accelerated killing by four in clinical use: isoniazid, ethionamide, delamanid pretomanid. ΔcinA was killed rapidly conditions known impede efficacy such during nutrient...
Caseous necrosis is a hallmark of tuberculosis (TB) pathology and creates niche for drug-tolerant persisters within the host. Cavitary TB high bacterial burden in caseum require longer treatment duration. An vitro model that recapitulates major features Mycobacterium (Mtb) would accelerate identification compounds with treatment-shortening potential. We have developed surrogate consisting lysed denatured foamy macrophages. Upon inoculation Mtb from replicating cultures, pathogen adapts to...
Tuberculosis lung lesions are complex and harbor heterogeneous microenvironments that influence antibiotic effectiveness. Major strides have been made recently in understanding drug pharmacokinetics pulmonary lesions, but the bacterial phenotypes arise under these conditions their contribution to tolerance poorly understood. A pharmacodynamic marker called RS ratio® quantifies ongoing rRNA synthesis based on abundance of newly synthesized precursor relative mature structural rRNA....
Fluoroquinolones represent the pillar of multidrug-resistant tuberculosis (MDR-TB) treatment, with moxifloxacin, levofloxacin, or gatifloxacin being prescribed to MDR-TB patients. Recently, several clinical trials “universal” drug regimens, aiming treat drug-susceptible and drug-resistant TB, have included a fluoroquinolone.
Abstract TBI-223, a novel oxazolidinone for tuberculosis, is designed to provide improved efficacy and safety compared linezolid in combination with bedaquiline pretomanid (BPaL). We aim optimize the dosing of TBI-223 within BPaL regimen enhanced therapeutic outcomes. investigated preclinical monotherapy, multidrug therapy, lesion penetration experiments describe its versus linezolid. A translational platform incorporating data from 4 clinical trials (NCT00396084, NCT02333799, NCT03086486,...
A dire need exists for novel drugs to treat Mycobacterium tuberculosis infection. In an effort build on our early efforts targeting the MenG enzyme within menaquinone biosynthetic pathway, we have pursued optimization of diaryl amide JSF-2911 address its poor metabolic stability and modest in vitro potency. hit evolution campaign focused modification amine substructure this compound, resulting a range analogues that been profiled extensively. Among these derivatives, JSF-4536 JSF-4898...
Tuberculosis (TB) remains one of the leading infectious causes death worldwide. Persistent bacterial populations in specific microenvironments within host hamper efficient TB chemotherapy. Caseum necrotic core closed granulomas and cavities pulmonary patients can harbor high burdens drug-tolerant Mycobacterium tuberculosis (MTB) bacilli, making them particularly difficult to sterilize. Here, we describe protocols for generation a surrogate matrix using lipid-rich macrophages mimic unique...
ABSTRACT By assessing the standard-of-care regimen for tuberculosis (TB) in BALB/c and C3HeB/FeJ mice, we demonstrate that rifampin, with or without pyrazinamide, is essential an effective bactericidal response suppression of resistance. Potency measurements vitro lipid-rich model a rabbit caseum assay recapitulate significance rifampin as sterilizing agent. These outcomes align clinical performance, thus emphasizing value predictive tools murine TB models human-like pathology.
We report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) in Mycobacterium tuberculosis Genetic and biochemical studies established KasA the primary target. The X-ray crystal structure KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites substrate-binding channel KasA. binding affinities its analog, 5g, which binds only once channel, were determined, along with KasA-5g structure. strongly augmented...
In the 1970s, inclusion of pyrazinamide (PZA) in drug regimen tuberculosis (TB) patients for first 2 mo achieved a drastic reduction therapy duration. Until now, however, mechanisms underlying PZA’s unique contribution to efficacy have remained controversial, and animal data vary across species. To understand how PZA kills bacterial populations present critical lung lesion compartments, we characterized rabbit model active TB, showing striking similarities types fates nonhuman primate models...
Nontuberculous mycobacterial pulmonary disease (NTM-PD) is a potentially fatal infectious requiring long treatment duration with multiple antibiotics and against which there no reliable cure. Among the factors that have hampered development of adequate drug regimens lack an animal model reproduces NTM lung pathology required for studying antibiotic penetration efficacy. Given documented similarities between tuberculosis immunopathology in patients, we first determined rabbit active key...
ABSTRACT BTZ-043, a suicide inhibitor of the Mycobacterium tuberculosis cell wall synthesis decaprenylphosphoryl-beta- D -ribose 2′ epimerase, is under clinical development as potential new anti-tuberculosis agent. BTZ-043 potent and bactericidal in vitro but has limited activity against non-growing bacilli rabbit caseum. To better understand its behavior vivo , was evaluated for efficacy spatial drug distribution single agent C3HeB/FeJ mouse model presenting with caseous necrotic pulmonary...