A5009996167- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- HIV Research and Treatment
- Drug Transport and Resistance Mechanisms
- HIV/AIDS Research and Interventions
- Cancer therapeutics and mechanisms
- Pneumocystis jirovecii pneumonia detection and treatment
- Antibiotic Resistance in Bacteria
- Sulfur Compounds in Biology
- Reproductive System and Pregnancy
- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
- interferon and immune responses
- Pharmacogenetics and Drug Metabolism
- Infectious Diseases and Tuberculosis
- Reproductive tract infections research
- Inhalation and Respiratory Drug Delivery
- HIV-related health complications and treatments
- Pneumonia and Respiratory Infections
- Polyamine Metabolism and Applications
- Reproductive Health and Contraception
- Neuroinflammation and Neurodegeneration Mechanisms
- Genetics, Aging, and Longevity in Model Organisms
- vaccines and immunoinformatics approaches
- Actinomycetales infections and treatment
Africa Health Research Institute
2017-2023
University of KwaZulu-Natal
1974-2021
Johns Hopkins Medicine
2015
Johns Hopkins University
2015
York College of Pennsylvania
1969
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...
How Mycobacterium tuberculosis (Mtb) rewires macrophage energy metabolism to facilitate survival is poorly characterized. Here, we used extracellular flux analysis simultaneously measure the rates of glycolysis and respiration in real time. Mtb infection induced a quiescent phenotype human monocyte-derived macrophages decelerated through TCA cycle. In contrast, with vaccine strain, M. bovis BCG, or dead glycolytic phenotypes greater flux. Furthermore, reduced mitochondrial dependency on...
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...
A key drug for the treatment of leprosy, clofazimine has recently been associated with highly effective and significantly shortened regimens multidrug-resistant tuberculosis (TB). Consequently, we hypothesized that may also shorten duration drug-susceptible TB. We conducted a controlled trial in mouse model TB chemotherapy comparing activity 6-mo standard regimen treatment, i.e., 2 mo daily rifampin, isoniazid, pyrazinamide, ethambutol followed by 4 rifampin 4-mo clofazimine-containing...
Abstract Tuberculosis chemotherapy is dependent on the use of antibiotic pyrazinamide, which being threatened by emerging drug resistance. Resistance mediated through mutations in bacterial gene pncA . Methods for testing pyrazinamide susceptibility are difficult and rarely performed, this means that full spectrum alleles confer clinical resistance to unknown. Here, we performed vitro saturating mutagenesis generate a comprehensive library PncA polymorphisms resultant from single-nucleotide...
The antileprosy drug clofazimine has shown potential for shortening tuberculosis treatment; however, the current dosing of is not evidence based, and optimal unknown. Our objective was to conduct a preclinical evaluation pharmacokinetics pharmacodynamics in mouse model tuberculosis, with goal providing useful information on future studies. Pharmacokinetic parameters were evaluated infected uninfected BALB/c mice. Pharmacodynamic Mycobacterium tuberculosis-infected mice that treated 12 weeks...
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 ubiquitous gasotransmitter hydrogen sulfide (H 2 S) has been recognized to play a crucial role in human health. Using cystathionine γ-lyase (CSE)-deficient mice, we demonstrate an unexpected of H S Mycobacterium tuberculosis ( Mtb ) pathogenesis. We showed that Mtb- infected CSE −/− mice survive longer than WT and support reduced pathology lower bacterial burdens the lung, spleen, liver. Similarly, vitro infection macrophages resulted colony forming units cells. Chemical complementation...
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...
Abstract Objectives There is a paucity of evidence regarding the optimal dosing anti-TB drugs in children. The aim this study was to identify pharmacokinetic parameters first-line and concentrations achieved after implementation 2010 WHO-recommended paediatric dosages. Methods We conducted prospective, observational children 10 years old or younger who were on isoniazid, rifampicin, pyrazinamide ethambutol therapy Durban, KwaZulu-Natal, South Africa. Blood collected at six timepoints over 24...
The anti-leprosy drug clofazimine has been shown to have antimicrobial activity against Mycobacterium tuberculosis and associated with treatment-shortening in both clinical preclinical studies of TB chemotherapy. However, a reported lack early bactericidal (EBA) patients raised questions regarding the usefulness as an anti-TB drug. Our objective was systematically evaluate EBA vitro vivo provide insight into how when this exerts its M. tuberculosis. We evaluated 14 day (i) at concentrations...
BACKGROUND. Tuberculosis (TB) kills more people than any other infection, and new diagnostic tests to identify active cases are required. We aimed discover verify novel markers for TB in nondepleted plasma.
Aim: We report the prevalence and effect of genetic variability on pharmacokinetic parameters isoniazid rifampicin. Materials & methods: Genotypes for SLCO1B1, NAT2, PXR, ABCB1 UGT1A genes were determined using a TaqMan® Genotyping OpenArray™. Nonlinear mixed-effects models used to describe drug pharmacokinetics. Results: Among 172 patients, 18, 43 34% classified as rapid, intermediate slow NAT2 acetylators, respectively. Of 58 patients contributing concentrations, rapid acetylators had 2.3-...
HIV cerebrospinal fluid (CSF) escape, where is suppressed in blood but detectable CSF, occurs when persists the CNS despite antiretroviral therapy (ART). To determine virus producing cell type and whether lowered CSF ART levels are responsible for we collected from 156 neurosymptomatic participants Durban, South Africa. We observed that 28% of with an undetectable viral load showed escape. detected host surface markers on envelope to cellular source first line regimen efavirenz,...
ABSTRACT Mycobactin biosynthesis in Mycobacterium tuberculosis facilitates iron acquisition, which is required for growth and virulence. The mycobactin inhibitor salicyl-AMS [5′- O -( N -salicylsulfamoyl)adenosine] inhibits M. vitro under iron-limited conditions. Here, we conducted a single-dose pharmacokinetic study monotherapy of with mice. Intraperitoneal injection yielded much better parameter values than oral administration did. Monotherapy at 5.6 or 16.7 mg/kg significantly inhibited...
We compared the pharmacokinetics of moxifloxacin during rifampicin co-treatment or when dosed alone in African patients with drug-susceptible recurrent TB.Patients intervention arm Improving Retreatment Success (IMPRESS) randomized controlled TB trial received 400 mg moxifloxacin, rifampicin, isoniazid and pyrazinamide treatment regimen. Moxifloxacin concentrations were measured plasma rifampicin-based again 4 weeks after completion, given as a single dose. concentration-time data analysed...
Early combination antiretroviral therapy (cART) reduces the size of viral reservoir in paediatric and adult HIV infection. Very early-treated children may have higher cure/remission potential.In an observational study 151 utero (IU)-infected infants KwaZulu-Natal, South Africa, whose treatment adhered strictly to national guidelines, 76 diagnosed via point-of-care (PoC) testing initiated cART at a median 26 h (IQR 18-38) 75 standard-of-care (SoC) laboratory-based 10 days 8-13). We analysed...
Objective: We sought to evaluate the utility of a point-of-care (POC) urine tenofovir (TFV) assay, developed objectively assess adherence, predict HIV drug resistance (HIVDR) in people failing first-line antiretroviral therapy (ART). Design: retrospectively analyzed TFV levels as biomarker adherence specimens collected during clinical trial that enrolled adults with virologic failure on ART Uganda and South Africa. Methods: Urine were from participants TFV-containing regimens who had viral...
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...
Placing seeds on a negatively charged conductor extended their viability during artificial aging. Such cathodic protection may reduce free radical attack by providing source of electrons. The results stupport the hypothesis damage to cellular components and are consistent with such being important in deteriorative senescence changes.
ABSTRACT Experimental and clinical studies have indicated that the antileprosy drug clofazimine may contribute treatment-shortening activity when included in tuberculosis treatment regimens. Clofazimine accumulates to high levels tissues, has a long half-life, remains body for months after administration is stopped. We hypothesized treatment, accumulated sustained antimicrobial cessation, we used BALB/c mouse model of chronic chemotherapy address this hypothesis. Mycobacterium -infected mice...
The distribution of N-acetyltransferase 2 gene (NAT2) polymorphisms varies considerably among different ethnic groups. Information on NAT2 single-nucleotide in the South African population is limited. We investigated and their effect isoniazid pharmacokinetics (PK) Zulu black HIV-infected Africans Durban, Africa. participants with culture-confirmed pulmonary tuberculosis (TB) were enrolled from two unrelated studies. Participants TB genotyped for 282C>T, 341T>C, 481C>T, 857G>A, 590G>A,...