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506 KiB

Open AccessArticle

Metabolism and Pharmacokinetics of the Anti-Tuberculosis Drug Ethionamide in a Flavin-Containing Monooxygenase Null Mouse

by Amy L. Palmer, Virginia L. Leykam, Andrew Larkin, Sharon K. Krueger, Ian R. Phillips, Elizabeth A. Shephard and David E. Williams

Pharmaceuticals 2012, 5(11), 1147-1159; https://doi.org/10.3390/ph5111147 - 25 Oct 2012

Cited by 15 | Viewed by 8547

Abstract

Multiple drug resistance (MDR) in Mycobacterium tuberculosis (mTB), the causative agent for tuberculosis (TB), has led to increased use of second-line drugs, including ethionamide (ETA). ETA is a prodrug bioactivated by mycobacterial and mammalian flavin-containing monooxygenases (FMOs). FMO2 is the major isoform in [...] Read more.

Multiple drug resistance (MDR) in Mycobacterium tuberculosis (mTB), the causative agent for tuberculosis (TB), has led to increased use of second-line drugs, including ethionamide (ETA). ETA is a prodrug bioactivated by mycobacterial and mammalian flavin-containing monooxygenases (FMOs). FMO2 is the major isoform in the lungs of most mammals, including primates. In humans a polymorphism exists in the expression of FMO2. FMO2.2 (truncated, inactive) protein is produced by the common allele, while the ancestral allele, encoding active FMO2.1, has been documented only in individuals of African and Hispanic origin, at an incidence of up to 50% and 7%, respectively. We hypothesized that FMO2 variability in TB-infected individuals would yield differences in concentrations and ratios of ETA prodrug and metabolites. In this study we assessed the impact of the FMO2 genetic polymorphism on the pharmacokinetics of ETA after administration of a single oral dose of ETA (125 mg/kg) to wild type and triple Fmo1/2/4-null mice, measuring levels of prodrug vs. metabolites in plasma collected from 0 to 3.5 h post-gavage. All mice metabolized ETA to ETA S-oxide (ETASO) and 2-ethyl-4-amidopyridine (ETAA). Wild type mice had higher plasma concentrations of metabolites than of parent compound (p = 0.001). In contrast, Fmo1/2/4-null mice had higher plasma concentrations of parent compound than of metabolites (p = 0.0001). Thus, the human FMO2 genotype could impact the therapeutic efficacy and/or toxicity of ETA. Full article

(This article belongs to the Special Issue Antituberculosis Drugs)

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179 KiB

Open AccessArticle

The Chemical Components of Sesbania grandiflora Root and Their Antituberculosis Activity

by Noviany Hasan, Hasnah Osman, Suriyati Mohamad, Wong Keng Chong, Khalijah Awang and Anis Safirah Mohd Zahariluddin

Pharmaceuticals 2012, 5(8), 882-889; https://doi.org/10.3390/ph5080882 - 23 Aug 2012

Cited by 55 | Viewed by 12249

Abstract

Three isoflavanoids, isovestitol (1), medicarpin (2), and sativan (3), along with another known compound, betulinic acid (4), were isolated from the root of Sesbania grandiflora. The structures of the isolated compounds were characterised by means of spectroscopic techniques (UV, IR, MS, ¹ [...] Read more.

Three isoflavanoids, isovestitol (1), medicarpin (2), and sativan (3), along with another known compound, betulinic acid (4), were isolated from the root of Sesbania grandiflora. The structures of the isolated compounds were characterised by means of spectroscopic techniques (UV, IR, MS, ¹H- and ¹³C-NMR, DEPT, COSY, HMQC, HMBC, and MS analysis). All the tested compounds 1–4 exhibited antituberculosis activity against Mycobacterium tuberculosis H37Rv, with MIC values of 50 µg/mL for compounds 1–3, and 100 µg/mL for compound 4, whereas, the methanol extract exhibited antituberculosis activity of 625 µg/mL. This is the first report on the occurrence of isoflavonoids in this plant and their antituberculosis activity. Full article

(This article belongs to the Special Issue Antituberculosis Drugs)

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Review

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Open AccessReview

The Role of Transport Mechanisms in Mycobacterium Tuberculosis Drug Resistance and Tolerance

by Jansy Passiflora Sarathy, Véronique Dartois and Edmund Jon Deoon Lee

Pharmaceuticals 2012, 5(11), 1210-1235; https://doi.org/10.3390/ph5111210 - 09 Nov 2012

Cited by 74 | Viewed by 15492

Abstract

In the fight against tuberculosis, cell wall permeation of chemotherapeutic agents remains a critical but largely unsolved question. Here we review the major mechanisms of small molecule penetration into and efflux from Mycobacterium tuberculosis and other mycobacteria, and outline how these mechanisms may [...] Read more.

In the fight against tuberculosis, cell wall permeation of chemotherapeutic agents remains a critical but largely unsolved question. Here we review the major mechanisms of small molecule penetration into and efflux from Mycobacterium tuberculosis and other mycobacteria, and outline how these mechanisms may contribute to the development of phenotypic drug tolerance and induction of drug resistance. M. tuberculosis is intrinsically recalcitrant to small molecule permeation thanks to its thick lipid-rich cell wall. Passive diffusion appears to account for only a fraction of total drug permeation. As in other bacterial species, influx of hydrophilic compounds is facilitated by water-filled open channels, or porins, spanning the cell wall. However, the diversity and density of M. tuberculosis porins appears lower than in enterobacteria. Besides, physiological adaptations brought about by unfavorable conditions are thought to reduce the efficacy of porins. While intracellular accumulation of selected drug classes supports the existence of hypothesized active drug influx transporters, efflux pumps contribute to the drug resistant phenotype through their natural abundance and diversity, as well as their highly inducible expression. Modulation of efflux transporter expression has been observed in phagocytosed, non-replicating persistent and multi-drug resistant bacilli. Altogether, M. tuberculosis has evolved both intrinsic properties and acquired mechanisms to increase its level of tolerance towards xenobiotic substances, by preventing or minimizing their entry. Understanding these adaptation mechanisms is critical to counteract the natural mechanisms of defense against toxic compounds and develop new classes of chemotherapeutic agents that positively exploit the influx and efflux pathways of mycobacteria. Full article

(This article belongs to the Special Issue Antituberculosis Drugs)

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200 KiB

Open AccessReview

Why and How the Old Neuroleptic Thioridazine Cures the XDR-TB Patient

by Leonard Amaral and Joseph Molnar

Pharmaceuticals 2012, 5(9), 1021-1031; https://doi.org/10.3390/ph5091021 - 17 Sep 2012

Cited by 10 | Viewed by 6666

Abstract

This mini-review provides the entire experimental history of the development of the old neuroleptic thioridazine (TZ) for therapy of antibiotic resistant pulmonary tuberculosis infections. TZ is effective when used in combination with antibiotics to which the initial Mycobacterium tuberculosis was resistant. Under proper [...] Read more.

This mini-review provides the entire experimental history of the development of the old neuroleptic thioridazine (TZ) for therapy of antibiotic resistant pulmonary tuberculosis infections. TZ is effective when used in combination with antibiotics to which the initial Mycobacterium tuberculosis was resistant. Under proper cardiac evaluation procedures, the use of TZ is safe and does not produce known cardiopathy such as prolongation of QT interval. Because TZ is cheap, it should be considered for therapy of XDR and TDR-Mtb patients in economically disadvantaged countries. Full article

(This article belongs to the Special Issue Antituberculosis Drugs)

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227 KiB

Open AccessReview

Chemotherapeutic Interventions Against Tuberculosis

by Neeraj Shakya, Gaurav Garg, Babita Agrawal and Rakesh Kumar

Pharmaceuticals 2012, 5(7), 690-718; https://doi.org/10.3390/ph5070690 - 28 Jun 2012

Cited by 31 | Viewed by 9460

Abstract

Tuberculosis is the second leading cause of infectious deaths globally. Many effective conventional antimycobacterial drugs have been available, however, emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has overshadowed the effectiveness of the current first and second line drugs. Further, currently [...] Read more.

Tuberculosis is the second leading cause of infectious deaths globally. Many effective conventional antimycobacterial drugs have been available, however, emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has overshadowed the effectiveness of the current first and second line drugs. Further, currently available agents are complicated by serious side effects, drug interactions and long-term administration. This has prompted urgent research efforts in the discovery and development of new anti-tuberculosis agent(s). Several families of compounds are currently being explored for the treatment of tuberculosis. This review article presents an account of the existing chemotherapeutics and highlights the therapeutic potential of emerging molecules that are at different stages of development for the management of tuberculosis disease. Full article

(This article belongs to the Special Issue Antituberculosis Drugs)

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