A5015383129- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Cancer therapeutics and mechanisms
- Infectious Diseases and Tuberculosis
- Quinazolinone synthesis and applications
- Infectious Diseases and Mycology
- Antibiotic Resistance in Bacteria
- Drug Transport and Resistance Mechanisms
- Pneumocystis jirovecii pneumonia detection and treatment
- Pharmacological Effects of Natural Compounds
- Synthesis and biological activity
- Phenothiazines and Benzothiazines Synthesis and Activities
- Diagnosis and treatment of tuberculosis
- Antibiotics Pharmacokinetics and Efficacy
- Pneumonia and Respiratory Infections
- Biochemical and Molecular Research
- RNA and protein synthesis mechanisms
- Fractional Differential Equations Solutions
- Antimicrobial Resistance in Staphylococcus
- vaccines and immunoinformatics approaches
- Bacterial Genetics and Biotechnology
- Cytokine Signaling Pathways and Interactions
- CNS Lymphoma Diagnosis and Treatment
- Pharmacological Effects and Toxicity Studies
- RNA modifications and cancer
Johns Hopkins University
2014-2024
Johns Hopkins Medicine
2012-2023
University of KwaZulu-Natal
2014-2015
P. D. Hinduja Hospital and Medical Research Centre
2003-2007
National Hospital
2004-2005
The discovery of Streptomyces-produced streptomycin founded the age tuberculosis therapy. Despite subsequent development a curative regimen for this disease, remains worldwide problem, and emergence multidrug-resistant Mycobacterium has prioritized need new drugs. Here we show that optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro vivo, by inhibiting DNA polymerase sliding clamp DnaN. We discovered resistance to...
Background The continued advance of antibiotic resistance threatens the treatment and control many infectious diseases. This is exemplified by largest global outbreak extensively drug-resistant (XDR) tuberculosis (TB) identified in Tugela Ferry, KwaZulu-Natal, South Africa, 2005 that continues today. It unclear whether emergence XDR-TB KwaZulu-Natal was due to recent inadequacies TB conjunction with HIV or other factors. Understanding origins drug this fatal XDR will inform prevention...
ABSTRACT The novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment of multidrug-resistant tuberculosis and is currently being studied as a component treatment-shortening regimens drug-susceptible tuberculosis. In limited number bedaquiline-treated patients reported to date, ≥4-fold upward shifts in MIC during have been attributed non-target-based mutations Rv0678 that putatively increase efflux through the MmpS5-MmpL5 pump. These also confer low-level...
PA-824 is a nitroimidazo-oxazine in clinical testing for the treatment of tuberculosis. We report that novel combination PA-824, moxifloxacin, and pyrazinamide cured mice more rapidly than first-line regimen rifampin, isoniazid, pyrazinamide. If applicable to humans, regimens containing this may radically shorten multidrug-resistant
A major priority in tuberculosis (TB) is to reduce effective treatment times and emergence of resistance. Recent studies macrophages zebrafish show that inhibition mycobacterial efflux pumps with verapamil reduces the bacterial drug tolerance may enhance efficacy.Using mice, a mammalian model known predict human responses, selecting conservative bioequivalent doses, we tested as an adjunctive together standard TB chemotherapy. As substrate for CYP3A4, which induced by rifampin, evaluated...
In previous experiments, replacing the 10-mg/kg of body weight daily dose rifampin with 7.5 to 10 mg/kg rifapentine in combinations containing isoniazid and pyrazinamide reduced duration treatment needed cure tuberculosis BALB/c mice by approximately 50% due rifapentine's more potent activity greater drug exposures obtained. present study, we performed dose-ranging comparisons bactericidal sterilizing activities rifapentine, alone combination or without ethambutol, C3HeB/FeJ mice, which...
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...
Rationale: Although observational studies suggest that clofazimine-containing regimens are highly active against drug-resistant tuberculosis, the contribution of clofazimine for treatment this disease has never been systematically evaluated.Objectives: Our goal was to directly compare activity a standard second-line drug regimen with or without addition in mouse model multidrug-resistant tuberculosis. comparative outcomes included time culture conversion lungs and percentage relapses after...
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...
Novel regimens combining bedaquiline and pretomanid with either linezolid (BPaL regimen) or moxifloxacin pyrazinamide (BPaMZ shorten the treatment duration needed to cure tuberculosis (TB) in BALB/c mice compared that of first-line regimen have yielded promising results initial clinical trials. However, independent contribution investigational new drug efficacy BPaMZ has not been examined, its BPaL examined only over first 2 months treatment. In present study, addition BL increased...
ABSTRACT The creation of new chemotherapeutic regimens that permit shortening the duration treatment is a major priority for antituberculosis drug development. In this study, we used murine model experimental tuberculosis therapy to determine whether incorporation investigational nitroimidazopyran PA-824 into standard first-line regimen has potential shorten 6-month treatment. As demonstrated previously, alone had significant bactericidal activity over first 2 months Moreover, substitution...
ABSTRACT To investigate the antagonism between isoniazid (INH) and rifampin (rifampicin) (RIF)-pyrazinamide (PZA) combination observed in Mycobacterium tuberculosis -infected mice, extensive pharmacokinetic studies of INH were performed followed by experiments to assess impact increasing doses on antimicrobial activity RIF-PZA combination. at 6.25 mg/kg body weight produced a maximum concentration drug serum ( C max ) value 4 μg/ml an area under concentration-time curve from 0 24 h (AUC 0-24...
Our inability to predict which mutations could result in antibiotic resistance has made it difficult rapidly identify the emergence of resistance, pre-existing resistant populations, and manage our use antibiotics effectively treat patients prevent or slow spread resistance. Here we investigated potential for against new antitubercular nitroimidazole prodrugs pretomanid delamanid emerge Mycobacterium tuberculosis, causative agent tuberculosis (TB). Deazaflavin-dependent nitroreductase (Ddn)...
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...
ABSTRACT The Mycobacterium avium complex is the most common cause of nontuberculous mycobacterial lung disease worldwide; yet, an optimal treatment regimen for M. infection has not been established. Clarithromycin accepted as cornerstone drug disease; however, good model systems, especially animal models, are needed to evaluate effective companion drugs. We performed a series experiments and use different mouse models (comparing BALB/c, C57BL/6, nude, beige mice) assess anti- activity single...
Mycobacterium tuberculosis cytochrome bd quinol oxidase (cyt bd), the alternative terminal of respiratory chain, has been identified as playing a key role during chronic infection and presents putative target for development novel antitubercular agents. Here, we report confirmation successful heterologous expression M. bd. The system was used to identify chemical series inhibitors based on 2-aryl-quinolone pharmacophore. Cytochrome displayed modest efficacy in growth suppression assays...
We compared the incidence of multidrug resistance in 150 consecutive Mycobacterium tuberculosis isolates obtained from a rural center (in Sakawar, India) and an urban tertiary care Mumbai, India). The study highlights alarmingly high percentage multidrug-resistant M. Mumbai (51%) as with that at (2%).
We report a high frequency (35%) of the Beijing genotype among multidrug-resistant isolates recovered in and around Mumbai, India. Further restriction fragment-length polymorphism typing showed that these strains were closely related. also Delhi (31% isolates). Our data indicate considerable ongoing transmission Mycobacterium tuberculosis Mumbai.
Rationale: Recent studies have demonstrated that combined substitutions of rifapentine for rifampin and moxifloxacin isoniazid in the standard, daily, short-course regimen rifampin, isoniazid, pyrazinamide produces stable cure 12 weeks or less. This study was designed to more precisely evaluate contribution rifapentine-based regimens.Objectives: We compared bactericidal activity treatment-shortening potential between regimens consisting plus administered either thrice-weekly daily.Methods:...
Daily rifapentine plus isoniazid-pyrazinamide in mice infected with Mycobacterium tuberculosis produces cure 3 months. Whether corresponds to latent infection contained by host immunity or true tissue sterilization is unknown.To determine the length of treatment rifapentine-isoniazid-pyrazinamide rifampin-isoniazid-pyrazinamide needed prevent relapse immune-deficient mice.Aerosol-infected BALB/c and nude were treated 5 days per week either 2 months rifapentine-based regimen followed...
In a randomized controlled trial in Ghana, treatment of Mycobacterium ulcerans infection with streptomycin (SM)-rifampin (RIF) for 8 weeks was compared SM-RIF 4 followed by RIF-clarithromycin (CLA) weeks. The extent the interaction RIF and CLA combined on pharmacokinetics two compounds is unknown this population therefore studied subset patients. Patients received at dose 7.5 mg/kg body weight once daily, rounded to nearest 125 mg. administered 10 mg/kg, 150 SM given 15 daily as an...
Background Vaccination with Mycobacterium bovis bacille Calmette-Guérin (BCG) is widely used to reduce the risk of childhood tuberculosis and has been reported have efficacy against two other mycobacterial diseases, leprosy Buruli ulcer caused by M. ulcerans (Mu). Studies in experimental models also shown some infection Mu. In mice, most studies use C57BL/6 strain that known develop good cell-mediated protective immunity. We hypothesized there may be differences vaccination between less...
Diagnosis of the neglected tropical disease, Buruli ulcer, can be made by acid-fast smear microscopy, specimen culture on mycobacterial growth media, polymerase chain reaction (PCR), and/or histopathology. All have drawbacks, including non-specificity and requirements for prolonged at 32°C, relatively sophisticated laboratory facilities, expertise, respectively. The causative organism, Mycobacterium ulcerans, produces a unique toxin, mycolactone A/B (ML) that detected thin layer...