clofazimine mechanism of action tuberculosis

J Exp Med 204:73–78. Mst Sumaia Khatun 1, Sadia Afrin2*, Md Shah Alam 3, 4* There is recent interest in understanding how CFZ works following the demonstration of its unique ability to shorten the treatment of MDR-TB. Exerts a slow bactericidal effect on Mycobacterium leprae (Hansen’s bacillus); inhibits mycobacterial growth and binds preferentially to mycobacterial DNA. Bactericidal against M. tuberculosis and M. marinum in vitro, but appears to be only bacteriostatic in vitro against other mycobacteria, including M. avium complex (MAC). Leprosy is a chronic bacterial infectious disease caused by Mycobacterium leprae ().This infection targets skin, peripheral nerves, and the eyes (5, 32).The mucosa of the upper respiratory tract, muscle, bones, and testes may also become involved during the course of this infection, particularly during the occurrence of a type 2 reaction or Erythema Nodosum Leprosum (ENL) (). Although the mechanism of action has not been characterized in M. leprae, the efficacy of thioamides in humans has made them possible alternative drugs for leprosy (51). mycolic acid is a type of long fatty acid that is a major structural component of cell walls unique to Mycobacteria ( Wikipedia: Mycolic acid ). clofazimine may exert an anti-mycobacterial effect against NTM as well as Mycobacterium tuberculosis or Mycobacterium leprae. CFZ is a hydrophobic riminophenazine that was initially synthesized as an anti-TB antibiotic. IL1 and IL1RA play a role in cancer progression and amelioration. Further studies are needed to address the role of rv1979c and rv2535c in clofazimine resistance and mechanisms of action. Chemotherapeutic activity of clofazimine and its analogues against Mycobacterium tuberculosis. Although the inclusion of the cationic amphiphilic, anti-mycobacterial agent, clofazimine, in the chemotherapeutic regimens of patients with multidrug-resistant tuberculosis (TB) has contributed to improved outcomes, concerns remain about the cardiotoxic potential of this agent. Mechanism of action. Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. The mechanism of action of clofazimine is not well understood, but the drug’s antibacterial activity may be mediated in part by its ability to bind mycobacterial DNA. Clofazimine has also been evaluated in the treatment of MAC lung disease and bacteremia. Clofazimine (CFZ) is a phenazine derivative used for treatment of leprosy, MDR-TB and XDR-TB. Mechanism of thioamide drug action against tuberculosis and leprosy. This requires the oxidation of reduced clofazimine, leading to the generation of the reactive oxygen species implicated in oxidative stress, such as superoxide and peroxide. The antileprosy drug clofazimine is also of interest for the treatment of multidrug-resistant tuberculosis. M. leprae resistant to clofazimine reported only rarely. It inhibits mycobacterial growth and binds preferentially to mycobacterial DNA. Here, we show that CFZ binds to mycobacterial integration host factor (mIHF), … Clofazimine's mechanism of action as an anti-mycobacterial drug is still not entirely understood. In both experiments, isoniazid was used as the positive control. In this regard, clofazimine is effective in both murine B16 melanoma and pancreatic cancer . ^ Fajardo TT, Guinto RS, Cellona RV, Abalos RM, Dela Cruz EC, Gelber RH. GDF: The Global Drug Facility2 is a global centralized procurement mechanism that offers quality-assured TB drugs at low prices LTBI: latent TB infection MDR-TB: multidrug-resistant TB, or TB resistant to isoniazid and rifampin, the two most powerful TB drugs Off-label: use of a drug for an indication other than the one for which it was approved Conclusions: Mutations in rv0678 are a major mechanism of clofazimine resistance. Clofazimine Mechanism : Clofazimine exerts a slow bactericidal effect on Mycobacterium leprae (Hansen's bacillus). Clofazimine-containing regimens have also been used and studied in the treatment of MDR-TB and XDR-TB, and they were found to promote cavity closure, accelerate sputum culture conversion, and improve treatment success rates [26, 32, 40, 41, 45]. Other medications for tuberculosis that can prolong the QT interval include fluoroquinolones and clofazimine. New drugs and drugs with a novel mechanism of action are desperately needed to shorten the duration of tuberculosis treatment, to prevent the emergence of drug resistance, and to treat multiple-drug-resistant strains of Mycobacterium tuberculosis. 1987. (Clofazimine (CFM), a riminophenazine drug, is primarily used in therapy for leprosy and Mycobacterium avium infections. Tuberculosis (TB) is an infectious disease that is caused by the bacterium Mycobacterium tuberculosis and it continues to be a serious threat to public health. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Absorption Designing strong regimens would help reduce the emergence of resistance. New drugs and drugs with a novel mechanism of action are desperately needed to shorten the duration of tuberculosis treatment, to prevent the emergence of drug resistance, and to treat multiple-drug-resistant strains of Mycobacterium tuberculosis.Recently, there has been renewed interest in clofazimine (CFZ). Trade Name: INH (generic) Drug Class: Antimycobacterial (anti-tuberculosis) Mechanism of Action: Inhibits biosynthesis of mycolic acid. clofazimine; tuberculosis; mouse model; tuberculosis treatment; experimental chemotherapy; Clofazimine is a riminophenazine dye developed in the 1950s by Vincent Barry and colleagues for the treatment of tuberculosis (TB) (1, 2).Despite being highly active against Mycobacterium tuberculosis in vitro and in mice, a limited number of studies led to the belief that clofazimine … cycling was the likely mechanism of action of clofazimine. Clofazimine (CFZ) is a rhimophenazine dye, originally developed for the treatment of tuberculosis. This drug has both antimicrobial and anti-inflammatory activity and has been found to have diverse uses in the treatment of leprosy, discoid lupus erythematosus, and pyoderma gangrenostun[1].CFZ is a broad- Cross-resistance between clofazimine … In vitro studies have shown that the 90% minimal inhibitory concentrations (MIC 90 ) of clofazimine for Mycobacterium intracellulare and M avium are 1.0 mg/L and 4.0 mg/L, respectively. 25 Clofazimine is active against other mycobacteria, this effect being more pronounced in vitro than in vivo, but the mechanism of its action against M. leprae is unknown. The present study describes a redox cycling pathway that involves the enzymatic reduction of CFZ by NDH-2, the primary respiratory chain NADH:quinone oxidoreductase of mycobacteria and nonenzymatic oxidation of reduced CFZ by O2 yielding CFZ and reactive oxygen species (ROS). A clinical trial of ethionamide and prothionamide for treatment of lepromatous leprosy. Overall, the activity of prothionamide (500 mg/day) against M. leprae was similar to that of dapsone and clofazimine, but … Mycobacterium 10. Tuberculosis drugs target various aspects of Mycobacterium tuberculosis biology, including inhibition of cell wall synthesis, protein synthesis, or nucleic acid synthesis. The present study describes a redox cycling pathway that in-volves the enzymatic reduction of CFZ by NDH-2, the primary respiratory chain NADH:quinone oxidoreductase of mycobac-teria and nonenzymatic oxidation of reduced CFZ by O We aimed to assess key considerations for the clinical and programmatic use of clofazimine (Cfz), a riminophenazine with antimycobacterial activity currently used to treat leprosy. Results 8,22 Alternatively, it has been postulated that clofazimine may interact with the bacterial cell membrane to disrupt cellular integrity and function. Objectives: The anti-leprosy drug clofazimine has been shown to have antimicrobial activity against Mycobacterium tuberculosis and has been associated with treatment-shortening activity in both clinical and preclinical studies of TB chemotherapy. The mechanism of action of clofazimine (CFZ), an antimy-cobacterial drug with a long history, is not well understood. However, the target of CFZ in mycobacteria has remained elusive. Roll-out of bedaquiline and clofazimine treatment in the setting of limited drug susceptibility testing could allow further spread of resistance. Treatment remains difficult and there has been no change in the duration of the standard regimen since the early 1980s. clofazimine (Cfz), a riminophenazine derived from a R-substitution at the imino group.9 Cfz has apparent anti-mycobacterial and anti-inflammatory activity, though its precise mechanism of action is still unclear.10 The drug is known to be highly lipophilic, accumulating in fatty tissues Also exerts anti-inflammatory properties in controlling erythema nodosum leprosum reactions; however, its precise mechanisms of action are unknown. Clofazimine (CFZ), an old hydrophobic riminophenazine, has a wide range of antimycobacterial activity ranging from leprosy to nontuberculous mycobacterial diseases. Clofazimine exerts a slow bactericidal effect on Mycobacterium leprae (Hansen's bacillus) due primarily to its action on the bacterial outer membrane, though there is some evidence that activity on the bacterial respiratory chain and ion transporters may play a role. [A203144] It also exerts anti-inflammatory properties due to the suppression of T-lymphocyte activity. Objectives Given the spread of multidrug-resistant tuberculosis (MDR-TB), new therapies are urgently needed, including the repurposing of existing drugs. It is the first member of a new class of drugs called the diarylquinolines. The mechanism of action of clofazimine in the treatment of inflammatory or pustular dermatosis (e.g., pyoderma gangrenosum) is unknown, but may be related to the drug’s enhancement of neutrophil and macrophage phagocytosis. Clofazimine is a riminophenazine antimycobacterial used to treat leprosy. However, its precise mechanisms of action are unknown. Tuberculosis (TB) remains a global threat with more than 9 million new infections. We evaluated the 14 day EBA of clofazimine (i) in vitro at concentrations ranging from 4 times below to 4 times above the MIC for M. tuberculosis and (ii) in vivo in infected BALB/c mice at doses ranging from 1.5 to 100 mg/kg/day, and serum clofazimine levels were measured. ^ Gelber RH. Our findings provide useful information for the design of new molecular tests for rapid detection of clofazimine resistance. Molecular mechanism of Clofazimine resistance in tuberculosis. 1.4.1 Clofazimine Mechanism of Action 10 1.4.2 Activity of Clofazimine against M tuberculosis 11 1.4.3 Clofazimine Physicochemical Properties 13 1.4.4 Pharmacokinetic Properties 14 1.4.5 Adverse Effects of Clofazimine 15 1.5 Targeted Pulmonary Delivery 16 However, TB47 might be powerful against M. tuberculosis when used in combination with other drugs, as its mechanism of action appears different from all proven anti-tuberculosis drugs. tial candidate to be repurposed is clofazimine (Cfz), a riminophenazine derived from an R-substitution at the imino group.9 Cfz has apparent antimycobacterial and anti-inflammatory activity, though its precise mechanism of action is still unclear.10 The drug is known to … Bedaquiline and clofazimine cross-resistance in southern Africa is emerging repeatedly, with evidence of onward transmission largely due to Rv0678 mutations in M tuberculosis. 4,23,24 Mechanism of Action. Therefore, we selected artemisone (Art) and clofazimine (CFZ) from a list of potential drugs under examination for their redox-oxidant mechanism of action coupled with a third partner, decoquinate (DQ) with a different mode of action to determine activity against TB when applied topically as a fixed-dose combination. Recently, there has been renewed interest in clofazimine (CFZ). Trinchieri has suggested that the study of intracellular infections such as tuberculosis and leprosy can also help us understand modern cancer immunotherapy [7, 8]. For some drugs, the mechanisms of action have not been fully identified. Clofazimine exerts a slow bactericidal effect on Mycobacterium leprae (Hansen's bacillus) due primarily to its action on the bacterial outer membrane, though there is some evidence that activity on the bacterial respiratory chain and ion transporters may play a role. Bedaquiline is … Am J Trop Med Hyg 74:457–461. Pharmacodynamics. Clofazimine and bedaquiline, two drugs used for the treatment of multidrug-resistant tuberculosis, are being considered as alternatives for the treatment of lung diseases caused by M. abscessus. 2006. We recently found that TB47 showed a very good synergistic activity with clofazimine against M. abscessus both in vitro and in mice model [ 24 ]. Clofazimine is bacteristatic and slowly bactericidal against M. leprae, similar to dapsone. Bedaquiline blocks the proton pump for ATP synthase of mycobacteria. The mechanism of action of clofazimine (CFZ), an antimycobacterial drug with a long history, is not well understood. Clofazimine (CFZ) is one such drug that has recently attracted interest against DR-TB. 1 It is ranked above HIV/AIDS as the single infectious agent that causes the most deaths worldwide. 2 It also exerts anti … 1 Introduction. CFZ has several advantages such as a favorable pharmacokinetic profile, dose-dependent side effects as well as low price. It also exerts anti-inflammatory properties in controlling erythema nodosum leprosum reactions. Moreover, many patients are unable to tolerate this treatment and discontinue therapy, increasing the risk of resistance.