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Principal Investigator: Mireille Kamariza
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $675,156
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Tuberculosis (TB) is second only to COVID-19 as the most lethal cause of death from a single infectious agent.
In 2020, an estimated 10 million people developed TB, nearly half a million of which were infected with drug-
resistant tuberculosis (DR-TB). Early detection of infection and drug resistance is critical to controlling
DR-TB as this enables rapid engagement into effective care. Unfortunately, only 71% of newly diagnosed
TB patients are ever tested for rifampicin resistance, and even fewer receive more comprehensive testing.
Additionally, despite improved treatment success rates for DR-TB globally, these success rates do not reflect
upstream losses resulting from undiagnosed (missing cases) and untreated patients. Currently, bacterial culture
and nucleic acid testing remain the primary methods for diagnosing infection, with smear microscopy being
phased out. However, these methods present significant limitations for diagnosing drug resistance such as
lengthy time-to-result for phenotypic tests, as well as the need for a priori knowledge of resistance mutations and
prohibitive cost for molecular tests. Clearly, there remains a critical need for a fast, accurate, and cost-effective
DST, particularly for resource-limited settings. To address this, we propose to design and develop a rapid
phenotypic drug susceptibility test that can be easily adapted in TB endemic regions. The trehalose-
based DST, termed Tre-DST, is based on novel trehalose probes, which require metabolic conversion to emit
fluorescent signals, giving them their unique ability to specifically detect live Mycobacterium tuberculosis
(Mtb). Agnostic to mechanism(s) of drug resistance, Tre-DST can be used with all WHO-recommended DRTB
drugs, as well as any future TB drugs as a companion diagnostic. In Aim 1, we will develop, characterize,
and optimize a family of novel fluorescent trehalose probes (3HC-Tre and RMR-Tre) that are specifically
designed to improve performance over DMN-Tre and to distinguish live Mtb, making them ideal as biomarkers
of drug susceptibility. We will also evaluate probe specificity to TB and probe performance across a variety of
bacteria typically present in oral mucosa. In Aim 2, we will develop and optimize Tre-DST as a multi-drug DST
for first- and second-line TB drugs. We will evaluate Tre-DST’s performance in accurately determining drug
resistance using drug susceptible and drug resistant Mtb strains, treated singly and in combination with the anti-
TB drugs that fulfill the WHO Target Product Profile (TPP) for next generation DST. We will also evaluate several
point-of-care (POC)-friendly detection methods to optimize efficiency and cost-effectiveness. Lastly, in Aim 3,
we will perform preliminary evaluation using banked clinical isolates in Johannesburg, South Africa to assess
the performance of Tre-DST in the field. We will evaluate pre-validated readout methods in this clinical study,
benchmarking the performance of Tre-DST against bacterial culture.
Terms: <Address><Antitubercular Agents><Antitubercular Drugs><Bacteria><Benchmarking><Best Practice Analysis><Biological Markers><Buccal Mucosa><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><CV-19><Caring><Cause of Death><Cell Communication and Signaling><Cell Signaling><Clinical><Clinical Evaluation><Clinical Research><Clinical Study><Clinical Testing><Combined Modality Therapy><Coronavirus Infectious Disease 2019><Country><Developing Countries><Developing Nations><Development><Diagnosis><Diagnostic><Diagnostic Method><Diagnostic Procedure><Diagnostic Technique><Disease><Disorder><Drug Controls><Drug Resistance Tuberculosis><Drug Resistant TB><Drug Resistant Tuberculosis><Drug resistance><Drug resistance in Mtb><Drug resistance in Mycobacterium Tuberculosis><Drug resistance in tuberculosis><Drug resistant M Tuberculosis><Drug resistant Mtb><Drug resistant Mycobacteria Tuberculosis><Drug usage><Drugs><Early Diagnosis><Evaluation><Extreme drug resistant tuberculosis><Extremely drug resistant tuberculosis><Family><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fluorescence><Friends><Future><Genotype><In Vitro><Individual><Infection><Infectious Agent><Intracellular Communication and Signaling><Knowledge><Label><Less-Developed Countries><Less-Developed Nations><Low-resource area><Low-resource community><Low-resource environment><Low-resource region><Low-resource setting><M tb><M tuberculosis><M tuberculosis H37Rv><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis H37Rv><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MDR Tuberculosis><MDR-TB><MTB infection><Measurement><Measures><Medication><Metabolic><Methods><Microscopy><Minimum Inhibitory Concentration measurement><Minimum Inhibitory Concentrations><Molecular><Mouth Mucosa><Mtb drug resistance><Multi-Drug Resistant Tuberculosis><MultiDrug Resistance Tuberculosis><Multidrug-Resistant Tuberculosis><Multimodal Therapy><Multimodal Treatment><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis H37Rv><Mycobacterium tuberculosis infection><Newly Diagnosed><Noise><Nucleic Acid Amplification Tests><Nucleic Acid Testing><Oral Mucosa><Oral mucous membrane structure><Outcome><Patients><Performance><Persons><Pharmaceutical Preparations><Phase><Phenotype><Predisposition><Protocol><Protocols documentation><Reader><Recommendation><Regimen><Reporting><Reproducibility><Research Resources><Research Specimen><Resistance><Resistance to infection><Resource-constrained area><Resource-constrained community><Resource-constrained environment><Resource-constrained region><Resource-constrained setting><Resource-limited area><Resource-limited community><Resource-limited environment><Resource-limited region><Resource-limited setting><Resource-poor area><Resource-poor community><Resource-poor environment><Resource-poor region><Resource-poor setting><Resources><Rifampicin resistance><Rifampicin resistant><Rifampin resistance><Rifampin resistant><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Signal Transduction><Signal Transduction Systems><Signaling><South Africa><Specificity><Specimen><Sputum><Susceptibility><System><TB diagnosis><TB diagnostics><TB drug resistance><TB drugs><TB infection><Testing><Third-World Countries><Third-World Nations><Time><Trehalose><Tuberculosis><Tuberculosis diagnosis><Tuberculostatic Agents><Under-Developed Countries><Under-Developed Nations><XDR-TB><XDR-Tuberculosis><anti-TB><anti-TB drugs><anti-tuberculosis><anti-tuberculosis drugs><antiTB><benchmark><bio-markers><biologic marker><biological signal transduction><biomarker><clinical applicability><clinical application><clinical test><combination therapy><combined modality treatment><combined treatment><companion diagnostics><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus infectious disease-19><cost><cost effective><cost effectiveness><design><designing><detection limit><detection method><detection procedure><detection technique><developing country><developing nation><developmental><diagnosed with TB><diagnosed with Tuberculosis><disseminated TB><disseminated tuberculosis><drug detection><drug resistance M Tuberculosis><drug resistance Mycobacteria Tuberculosis><drug resistance in TB><drug resistant><drug resistant M.tb><drug resistant in tuberculosis><drug testing><drug use><drug/agent><early detection><extensively drug resistant TB><extensively drug resistant tuberculosis><flow cytophotometry><improved><infection due to Mycobacterium tuberculosis><infection resistance><infectious organism><mtb><multi-modal therapy><multi-modal treatment><multidrug-resistant TB><next generation><novel><oral mucosae><oral mucosal><performance tests><point of care><pre-pandemic><programs><research clinical testing><resistance mutation><resistance strain><resistance to Drug><resistance to rifampicin><resistance to rifampin><resistant><resistant mutation><resistant strain><resistant to Drug><resistant to rifampicin><resistant to rifampin><sample collection><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><specimen collection><success><sugar><tuberculosis diagnostics><tuberculosis drugs><tuberculosis infection><tuberculous spondyloarthropathy>