The Antimycobacterial Activity of B 663

103

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). In this study, we utilized the C3HeB/FeJ mouse model, possessing highly organized, hypoxic pulmonary granulomas with caseous necrosis, to evaluate CFZ monotherapy in comparison to results with BALB/c mice, which form only multifocal, coalescing cellular aggregates devoid of caseous necrosis. While CFZ treatment was highly effective in BALB/c mice, its activity was attenuated in the lungs of C3HeB/FeJ mice. This lack of efficacy was directly related to the pathological progression of disease in these mice, since administration of CFZ prior to the formation of hypoxic, necrotic granulomas reconstituted bactericidal activity in this mouse strain. These results support the continued use of mouse models of tuberculosis infection which exhibit a granulomatous response in the lungs that more closely resembles the pathology found in human disease.

Section: Discussionmentioning

confidence: 99%

Limited Activity of Clofazimine as a Single Drug in a Mouse Model of Tuberculosis Exhibiting Caseous Necrotic Granulomas

Irwin

Gruppo

Brooks

et al. 2014

103

“…CFM and analogs have been shown to demonstrate activity in vitro against most mycobacteria (38), as well as some Gram-positive species (19). Against replicating M. tuberculosis, CFM demonstrates activity in vitro against both drug-sensitive and drug-resistant strains (8,29) and activity against M. tuberculosis replicating inside macrophages (44). Although activity against replicating and intracellular bacteria is desirable in an antitubercular drug, it is widely believed that subpopulations of nonreplicating or slowly replicating bacteria, which may be intracellular, extracellular, or both, exist during TB infection and are refractory to many antibiotics.…”

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confidence: 99%

“…One such compound is clofazimine (CFM), a riminophenazine and marketed antimycobacterial drug used since 1962 in the treatment of leprosy (16,17) and, more recently, in the treatment of Mycobacterium avium complex infection (16) and MDR-TB (43). CFM, a redox active compound, with dye properties, was specifically designed as an antitubercular to accumulate within cells of the mononuclear phagocyte system (MPS) and kill intracellular bacteria (6)(7)(8). CFM and analogs have been shown to demonstrate activity in vitro against most mycobacteria (38), as well as some Gram-positive species (19).…”

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confidence: 99%

Clofazimine Analogs with Efficacy against Experimental Tuberculosis and Reduced Potential for Accumulation

Zheng

Wang

et al. 2011

154

149

The global tuberculosis crisis urgently demands new, efficacious, orally available drugs with the potential to shorten and simplify the long and complex treatments for drug-sensitive and drug-resistant disease. Clofazimine, a riminophenazine used for many years to treat leprosy, demonstrates efficacy in animal models of tuberculosis via a novel mode of action. However, clofazimine's physicochemical and pharmacokinetic properties contribute to side effects that limit its use; in particular, an extremely long half-life and propensity for tissue accumulation together with clofazimine's dye properties leads to unwelcome skin discoloration. We recently conducted a systematic structure-activity study of more than 500 riminophenazine analogs for antiMycobacterium tuberculosis activity. We describe here the characteristics of 12 prioritized compounds in more detail. The new riminophenazine analogs demonstrated enhanced in vitro activity compared to clofazimine against replicating M. tuberculosis H37Rv, as well as panels of drug-sensitive and drug-resistant clinical isolates. The new compounds demonstrate at least equivalent activity compared to clofazimine against intracellular M. tuberculosis and, in addition, most of them were active against nonreplicating M. tuberculosis. Eleven of these more water-soluble riminophenazine analogs possess shorter half-lives than clofazimine when dosed orally to mice, suggesting that they may accumulate less. Most importantly, the nine compounds that progressed to efficacy testing demonstrated inhibition of bacterial growth in the lungs that is superior to the activity of an equivalent dose of clofazimine when administered orally for 20 days in a murine model of acute tuberculosis. The efficacy of these compounds, along with their decreased potential for accumulation and therefore perhaps also for tissue discoloration, warrants further study. Despite global efforts, tuberculosis (TB) remains responsible for the second greatest number of deaths due to an infectious disease with 1.7 million deaths reported due to TB in 2009 (45). Of particular concern, the increasing prevalence of TB caused by multidrug-resistant (MDR) and extensively drugresistant (XDR) strains of Mycobacterium tuberculosis puts at risk hard-won gains to public health. MDR-TB treatment regimens, where available, comprise multiple expensive drugs with limited efficacy and significant toxicity that must be administered by both oral and parenteral routes for up to 24 months (30). Treatment of drug-sensitive TB is also long and complex, requiring at least 6 months of a four-drug regimen to achieve a stable cure. The first-line TB drugs are poorly tolerated, reducing compliance and increasing the risk of resistance development. New TB drugs that are safe, orally available, have novel modes of action and efficacy sufficient to simplify and shorten the regimen required to cure TB would impact both patients and TB control by providing improved treatment for drug-resistant TB and by providing a faster, more tolerable cure for dr...

“…It is also useful in the antimicrobialcombination chemotherapy of Mycobacterium avium infections in AIDS patients (1). Clofazimine also inhibits the growth of tubercle bacilli in vitro and in animal models of experimental infection (7).…”

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confidence: 99%

“…As a consequence of its highly lipophilic nature and redox potential (-0.18 V at pH 7), it has been proposed that intracellular generation of hydrogen peroxide by redoxcycling mechanisms may contribute to the antimicrobial activity of clofazimine (5). It has also been reported that clofazimine binds to the guanine bases of DNA, thereby blocking the template function of the DNA, leading to inhibition of proliferation (17).…”

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confidence: 99%

Antimicrobial activities of clofazimine and B669 are mediated by lysophospholipids

Rensburg

Jooné

O’Sullivan

et al. 1992

The susceptibilities of a range of gram-positive and gram-negative microbial pathogens to clofazimine and its analog B669 (0.1 to 32 pg/ml), as well as the effects of these agents on membrane phospholipid metabolism in Staphylococcus aureus and Escherichia coli, have been investigated in vitro. Gram-positive bacteria were found to be generally susceptible to these agents, whereas gram-negative organisms were uniformly resistant. Exposure of S. aureus to both agents (1 to 5 ,ug/ml), especially B669, caused dose-related enhancement of the activity of phospholipase A2, according to an increase in the release of 3H-radiolabeled arachidonate and lysophosphatidylethanolamine (