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Principal Investigator: Kyle H Rohde
Organization: UNIVERSITY OF CENTRAL FLORIDA
Fiscal Year: 2024
Award: $237,288
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is responsible for staggering levels of
morbidity and mortality, with ~1.7 million deaths and ~10 million new cases each year. The current TB
regimens for drug susceptible strains, entailing multidrug cocktails for ≥4 months, leave much to be
desired. The cost and logistics of administering standard of care regimens over many months and the
inability of many patients to tolerate the debilitating side effects further complicate the clinical control of
TB. The lingering negative impacts of the COVID pandemic on TB control efforts and increasing challenge
of multidrug-resistant Mtb strains, which have only a ~50% treatment success rate, further highlight the
urgent need for better antibiotics to tackle this problem. Even our definition of what “better” means has
shifted based on recent appreciation of the heterogeneity of mycobacteria subpopulations that must be
eradicated, including replicating and non-replicating bacilli residing both extracellularly and within host cells
in diverse microenvironments. Thus, effective drug combinations must not only access mycobacteria within
different niches and layers of granulomas but also be able to kill Mtb in many distinct metabolic states while
minimizing the emergence of resistance. In order to meet this urgent need for game-changing new
treatment options for TB, it is imperative to maintain a robust pipeline of new anti-TB drug candidates with
the potential to meet these demanding performance criteria. This project seeks to address this need by
building on our recent discovery of a first-in-class series of compounds that kill Mtb via inhibition of a well-
validated but underexploited target enzyme essential for cell wall synthesis. Thus far, we have
demonstrated sub-micromolar potency, enhanced potency against Mtb within macrophages, high
specificity for Mtb, and high selectivity over mammalian cells. We have strong evidence that these
compounds act via inhibition of an essential enzyme involved in mycolic acid biosynthesis for which there
are currently no viable preclinical candidates. The first major goal of this project is hit-to-lead optimization
and elucidation of structure-activity relationships, using whole cell potency and ADME/PK properties as
key drivers of compound prioritization. Secondly, we will employ orthogonal approaches to further validate
the target and ensure that optimized lead compounds remain on-target. Successful completion of this
project will set the stage for subsequent lead optimization and in vivo efficacy studies of a promising new
class of cell-wall targeting TB antibiotics.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Acute><Address><Anabolism><Antibiotic Agents><Antibiotic Drugs><Antibiotic Therapy><Antibiotic Treatment><Antibiotics><Antibiotics against tuberculosis><Antitubercular Antibiotics><Antitubercular Drugs><Bacillus><Bacteria><Bioavailability><Biochemical><Biological Availability><COVID-19 affected><COVID-19 consequence><COVID-19 effect><COVID-19 impact><COVID-19 impacted><COVID-19 pandemic affected><COVID-19 pandemic consequence><COVID-19 pandemic effects><COVID-19 pandemic impact><COVID-19 pandemic impacted><COVID-19 virus><COVID19 virus><CRISPR interference><CRISPR-dCas9-mediated repression><CRISPR/dCas9 interference><CRISPR/dCas9-mediated transcriptional inhibition><CRISPRi><Cell Body><Cell Wall><Cells><Cessation of life><Chronic><Clinical><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats interference><CoV-2><CoV2><Cyclicity><Cytolysis><Death><Development><Disease><Disorder><Docking><Drug Combinations><Drug Kinetics><Drug Targeting><Drug resistance><Drug resistance in Mtb><Drug resistance in Mycobacterium Tuberculosis><Drug resistant M Tuberculosis><Drug resistant Mtb><Drug resistant Mycobacteria Tuberculosis><Drugs><Ensure><Enzyme Gene><Enzymes><Equilibrium><Evaluation><Extreme drug resistant tuberculosis><Extremely drug resistant tuberculosis><Future><Genetic><Genus Mycobacterium><Goals><Granuloma><Granulomatous Lesion><Heterogeneity><In Vitro><Infection><Infectious Agent><Isonicotinic Acid Hydrazide><Knowledge><Lead><Lesion><Logistics><Lysis><M tb><M tuberculosis><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MDR Mtb><MDR Mycobacterium tuberculosis><MDR Tuberculosis><MDR-TB><MTB infection><Macrophage><Mammalian Cell><Medication><Metabolic><Miscellaneous Antibiotic><Modeling><Morbidity><Morbidity - disease rate><Mtb drug resistance><Multi-Drug Resistant Tuberculosis><Multi-drug resistant M. Tuberculosis><Multi-drug resistant Mtb><Multi-drug resistant Mycobacterium tuberculosis><MultiDrug Resistance Tuberculosis><Multidrug resistant M. Tuberculosis><Multidrug resistant Mtb><Multidrug resistant Mycobacterium tuberculosis><Multidrug-Resistant Tuberculosis><Multiple drug resistance Mycobacteria Tuberculosis><Multiple drug resistant Mycobacteria Tuberculosis><Mycobacterium><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Mycolic Acid><Mφ><Natural Products><Oral><Patients><Pb element><Performance><Periodicity><Permeability><Persons><Phagosomes><Pharmaceutical Preparations><Pharmacokinetics><Phenotype><Physiologic Availability><Predisposition><Property><Public Health><Regimen><Reporting><Research><Resistance><Resistance development><Resistant development><Rhythmicity><Route><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Safety><Series><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Specificity><Structure-Activity Relationship><Susceptibility><Synthesis Chemistry><Synthetic Chemistry><TB antibiotics><TB drugs><TB infection><TB therapy><TB treatment><Testing><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tuberculosis><Tuberculosis antibiotics><Validation><Variant><Variation><Virulence><Work><Wuhan coronavirus><XDR-TB><XDR-Tuberculosis><analog><anti-TB drugs><anti-microbial><anti-tuberculosis drugs><antibiotic against TB><antibiotic tolerance><antimicrobial><bacterial disease treatment><bacterial infectious disease treatment><bactericidal><bactericide><balance><balance function><biosynthesis><cell type><chemical structure function><coronavirus disease 2019 consequence><coronavirus disease 2019 effect><coronavirus disease 2019 impact><coronavirus disease 2019 pandemic consequence><coronavirus disease 2019 pandemic impact><coronavirus disease 2019 virus><coronavirus disease-19 impact><coronavirus disease-19 virus><cost><developing resistance><developmental><disseminated TB><disseminated tuberculosis><drug candidate><drug discovery><drug resistance M Tuberculosis><drug resistance Mycobacteria Tuberculosis><drug resistant><drug resistant M.tb><drug/agent><effects following the COVID-19 pandemic><efficacy study><entire genome><extensive drug resistance><extensively drug resistant><extensively drug resistant TB><extensively drug resistant tuberculosis><extracellular><extreme drug resistance><full genome><genome sequencing><genotoxicity><hCoV19><heavy metal Pb><heavy metal lead><impact of the SARS-CoV-2 pandemic><in silico><in vivo><in vivo Model><infection due to Mycobacterium tuberculosis><infectious organism><inhibitor><insight><isoniazid><knock-down><knockdown><lead optimization><mortality><mtb><multidisciplinary><multidrug-resistant TB><mutant><mycobacterial><nCoV2><naturally occurring product><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pandemic><pandemic disease><pharmacologic><pre-clinical><preclinical><repressing CRISPR-dCas9 system><resistance strain><resistance to Drug><resistant><resistant strain><resistant to Drug><screening><screenings><side effect><standard of care><stem><structure function relationship><success><sulfamate><synergism><tolerance to antibiotics><tolerate antibiotics><treat M. tuberculosis><treat Mtb><treat Mycobacterium tuberculosis><treat tb><treat tuberculosis><tuberculosis drugs><tuberculosis infection><tuberculosis therapy><tuberculosis treatment><tuberculous spondyloarthropathy><validations><whole genome>