A5077049669- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Biochemical and Molecular Research
- Cancer therapeutics and mechanisms
- Drug Transport and Resistance Mechanisms
- Sulfur Compounds in Biology
- Pneumocystis jirovecii pneumonia detection and treatment
- Quinazolinone synthesis and applications
- Polyamine Metabolism and Applications
- Antibiotic Resistance in Bacteria
- Parasitic Infections and Diagnostics
- Synthesis and bioactivity of alkaloids
- Chemical Synthesis and Analysis
- Inhalation and Respiratory Drug Delivery
- HIV/AIDS drug development and treatment
- Phenothiazines and Benzothiazines Synthesis and Activities
- Crystallization and Solubility Studies
- Chronic Lymphocytic Leukemia Research
- Microbial Natural Products and Biosynthesis
- Health and Well-being Studies
- Infectious Diseases and Tuberculosis
- interferon and immune responses
- Vibrio bacteria research studies
- vaccines and immunoinformatics approaches
- Amino Acid Enzymes and Metabolism
Janssen (United Kingdom)
2024-2025
Janssen (Belgium)
2020-2025
Africa Health Research Institute
2017-2021
University of KwaZulu-Natal
2018-2021
Stellenbosch University
2012
Abstract The Mycobacterium tuberculosis (Mtb) electron transport chain (ETC) has received significant attention as a drug target, however its vulnerability may be affected by flexibility in response to disruption. Here we determine the effect of ETC inhibitors bedaquiline, Q203 and clofazimine on Mtb ETC, value measuring Mtb’s respiration using extracellular flux technology. We find that rapidly reroutes around inhibition these drugs increases total maintain ATP levels. Rerouting is possible...
Highlights•WhiB3 regulates EGT production and maintains bioenergetic homeostasis in Mtb•EGT modulates drug sensitivity protects Mtb from diverse oxidative stressors•EGT is essential for survival macrophages miceSummaryThe mechanisms by which Mycobacterium tuberculosis (Mtb) metabolic equilibrium to survive during infection upon exposure antimycobacterial drugs are poorly characterized. Ergothioneine (EGT) mycothiol (MSH) the major redox buffers present Mtb, but contribution of virulence...
Abstract Hydrogen sulfide (H 2 S) is involved in numerous pathophysiological processes and shares overlapping functions with CO • NO. However, the importance of host-derived H S microbial pathogenesis unknown. Here we show that Mtb -infected mice deficient S-producing enzyme cystathionine β-synthase (CBS) survive longer reduced organ burden, pharmacological inhibition CBS reduces bacillary load mice. High-resolution respirometry, transcriptomics mass spectrometry establish stimulates...
The immunometabolic mechanisms underlying suboptimal T cell immunity in tuberculosis remain undefined. Here, we examine how chronic Mycobacterium (Mtb) and M. bovis BCG infections rewire metabolic circuits alter effector functions lung CD8+ cells. As Mtb infection progresses, mitochondrial metabolism deteriorates cells, resulting an increased dependency on glycolysis that potentiates inflammatory cytokine production. Over time, these cells develop bioenergetic deficiencies reflect...
New drugs are needed to control the current tuberculosis (TB) pandemic caused by infection with
Mycobacterium tuberculosis (MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing structure-based design small-molecule inhibitors. Herein, we disclose MTb whole-cell structure–activity relationships (SARs) series 2-mercapto-quinazolinones target ndh encoded with nanomolar potencies. The...
Abstract The approval of bedaquiline (BDQ) for the treatment tuberculosis has generated substantial interest in inhibiting energy metabolism as a therapeutic paradigm. However, it is not known precisely how BDQ triggers cell death Mycobacterium ( Mtb) . Using 13 C isotopomer analysis, we show that BDQ-treated Mtb redirects central carbon to induce metabolically vulnerable state susceptible genetic disruption glycolysis and gluconeogenesis. Metabolic flux profiles indicate dependent on ATP...
We deleted subunits I (cydA) and II (cydB) of the Mycobacterium tuberculosis cytochrome bd menaquinol oxidase. The resulting ΔcydA ΔcydAB mutants were hypersusceptible to compounds targeting mycobacterial bc1 menaquinol-cytochrome c oxidoreductase exhibited bioenergetic profiles indistinguishable from strains deficient in ABC-type transporter, CydDC, predicted be essential for assembly. These results confirm CydAB CydDC as potential targets drugs aimed at inhibiting a terminal respiratory...
The emergence of multi-drug (MDR-TB) and extensively-drug resistant tuberculosis (XDR-TB) is a major threat to the global management (TB) worldwide. New chemical entities are need treat drug-resistant TB. In this study, mode action new, potent quinazoline derivatives was investigated against Mycobacterium (M. tb). Four 11626141, 11626142, 11626252 11726148 showed good activity (MIC ranging from 0.02-0.09 μg/mL) low toxicity (TD50 ≥ 5μg/mL) in vitro M. tb strain H37Rv HepG2 cells,...
Signals modulating the production of Mycobacterium tuberculosis (Mtb) virulence factors essential for establishing long-term persistent infection are unknown. The WhiB3 redox regulator is known to regulate Mtb factors, however mechanisms this modulation To advance our understanding involved in regulation, we performed vitro, intraphagosomal and infected host expression analyses. Our analyses conjunction with extracellular flux demonstrated that maintains bioenergetic homeostasis response...
<title>Abstract</title> Drug-resistant tuberculosis (TB) continues to challenge treatment options, necessitating the exploration of new compounds novel targets. The mycobacterial respiratory complex cytochrome bc1:aa3 has emerged as a promising target, exemplified by success first-in-class inhibitor Q203 in phase 2 clinical trial. However, fully exploit potential this target and identify best-in-class more need evaluation. Here, we introduce JNJ-2901, M. bc1:aa3, demonstrating activity...
Abstract Drug-resistant tuberculosis (TB) continues to challenge treatment options, necessitating the exploration of new compounds novel targets. The mycobacterial respiratory complex cytochrome bc 1 :aa 3 has emerged as a promising target, exemplified by success first-in-class inhibitor Q203 in phase 2 clinical trials. However, fully exploit potential this target and identify best-in-class more need evaluation. Here, we introduce JNJ-2901, analogue, that demonstrates activity against...
Abstract The quinolone decoquinate is coadministered with feed for treatment of parasites which cause coccidiosis in poultry. However, from a drug-development perspective, the biological activity often not adequately exploited due to poor physicochemical properties. Here we convert into N -alkyl amides that, contrast decoquinate, are active against tuberculosis bacterium MIC 90 values ranging 1.4 3.64 µM, and quinoline O -carbamates apicomplexan that malaria, toxoplasmosis, neosporosis IC 50...
ABSTRACT The World Health Organization’s goal to combat tuberculosis (TB) is hindered by the emergence of anti-microbial resistance, therefore necessitating exploration new drug targets. Multidrug regimens are indispensable in TB therapy as they provide synergetic bactericidal effects, shorten treatment duration, and reduce risk resistance development. research within our European RespiriTB consortium explores Mycobacterium energy metabolism identify candidates that synergize with...
H2S is a potent gasotransmitter in eukaryotes and bacteria. Host-derived has been shown to profoundly alter M. tuberculosis (Mtb) energy metabolism growth. However, compelling evidence for endogenous production of its role Mtb physiology lacking. We show that multidrug-resistant drug-susceptible clinical strains produce H2S, whereas non-pathogenic smegmatis barely detectable. identified Rv3684 (Cds1) as an H2S-producing enzyme cds1 disruption reduces, but does not eliminate, production,...
Abstract Tuberculosis (TB) remains one of the leading infectious disease killers in world. The ongoing development novel anti-TB medications has yielded potent compounds that often target single sites with well-defined mechanisms action. However, despite identification resistance-associated mutations through deconvolution studies, comparing these findings diverse Mycobacterium tuberculosis populations observed clinical settings is challenging. To address this gap, we constructed an...
MshB is the N-acetyl-1-D-myo-inosityl-2-amino-2-deoxy-D-glucopyranoside (GlcNAc-Ins) deacetylase active as one of enzymes involved in biosynthesis mycothiol (MSH), a protective low molecular weight thiol present only Mycobacterium tuberculosis and other actinomycetes. In this study, structural analogues GlcNAc-Ins which inosityl moiety replaced by chromophore were synthesized evaluated alternate substrates MshB, with goal identifying compound that would be useful high-throughput assays...
Abstract H 2 S is a potent gasotransmitter in eukaryotes and bacteria. Host-derived has been shown to profoundly alter M. tuberculosis ( Mtb ) energy metabolism growth. However, compelling evidence for endogenous production of its role physiology lacking. We show that multidrug-resistant drug-susceptible clinical strains produce S, whereas non-pathogenic smegmatis barely detectable. identified Rv3684 (Cds1) as an S-producing enzyme cds1 disruption reduces, but does not eliminate, production,...
<title>Abstract</title> Tuberculosis remains the leading cause of death from an infectious disease, responsible for 1.3 million deaths annually. Here, we report discovery a first-in-class small molecule inhibitor targeting PurF, first enzyme in mycobacterial de novo purine biosynthesis pathway. Our lead candidate, JNJ-6640, exhibited nanomolar bactericidal activity vitro. Using array comprehensive genetic and biochemical approaches, confirmed JNJ-6640 was highly selective PurF compared to...
<title>Abstract</title> Recent efforts to improve tuberculosis (TB) treatment options have focused on developing molecules with novel mechanisms of action and identifying optimal regimens. Inhibition Mycobacterium cytochrome bc1 oxidase has emerged as a promising therapeutic target that could potentially contribute improved TB combination Using relapsing mouse model, we demonstrate inhibitors serve effective partner drugs, enhancing regimen sterilisation. We propose several strategies for...