Clofazimine: current status and future prospects

Abstract

Clofazimine, a lipophilic riminophenazine antibiotic, possesses both antimycobacterial and anti-inflammatory activities. However, its efficacy has been demonstrated only in the treatment of leprosy, not in human tuberculosis, despite the fact that this agent is impressively active in vitro against multidrug-resistant strains of Mycobacterium tuberculosis. Recent insights into novel targets and mechanisms of antimicrobial and anti-inflammatory activity coupled with the acquisition of innovative drug delivery technologies have, however, rekindled interest in clofazimine as a potential therapy for multidrug- and extensively multidrug-resistant tuberculosis in particular, as well as several autoimmune diseases. The primary objective of this review is to critically evaluate these recent developments and to assess their potential impact on improving the therapeutic efficacy and versatility of clofazimine.

Multiscale Distribution and Bioaccumulation Analysis of Clofazimine Reveals a Massive Immune System-Mediated Xenobiotic Sequestration Response

“…phage dependent, active xenobiotic sequestration response associated with the intracellular accumulation of clofazimine, the upregulation of IL-1RA (34,35,52) could explain the potent antiinflammatory effects of clofazimine reported in clinical studies (3,4). IL-1RA inhibits the binding of soluble IL-1␣ and IL-1␤ to the proinflammatory interleukin-1 (IL-1) receptor (34,35,52), leading to a pronounced, systemic anti-inflammatory activity.…”

“…lofazimine is an orally bioavailable, poorly soluble, highly lipophilic (logP Ͼ 7) antibiotic drug with a very long pharmacokinetic half-life (1)(2)(3)(4)(5)(6). It was first marketed in 1969 as "Lamprene," and in 1983 it was recommended by the World Health Organization as one of the components of multidrug therapy against leprosy (7).…”

Synthesis and Biological Evaluation of Novel 2-Methoxypyridylamino-Substituted Riminophenazine Derivatives as Antituberculosis Agents

“…We also concluded that an electron-withdrawing group at the para-position of the phenyl ring at the N-5 position was beneficial to antituberculosis activity [9]. Previously, O'Sullivan and coworkers found that compounds bearing a 3,4-dichlorophenyl or 3,4,5-trichlorophenyl group at the N-5 position and a tetramethylpiperidyl group at the C-3 position, such as compound B4100 (Figure 1), possessed improved antituberculosis activity as compared to CFZ [10,11]. These work prompted us to further investigate the effect of the halogen atoms on the phenyl ring at the N-5 position for antituberculosis activity based on our 2-methoxypyridylamino-substituted riminophenazine system.…”

Effects of clofazimine on planktonic and biofilm growth of Mycobacterium tuberculosis and Mycobacterium smegmatis

“…The antimycobacterial riminophenazine agent clofazimine is categorised by the World Health Organization (WHO) as a last-resort option (group 5 drug) in the treatment of multidrug-resistant TB (MDR-TB), largely because of its poor pharmacokinetic properties [12,13]. However, this antibiotic possesses several properties that may enable it to target both biofilm-forming as well as biofilminsulated organisms, including those that are MDR [12][13][14].…”

“…However, this antibiotic possesses several properties that may enable it to target both biofilm-forming as well as biofilminsulated organisms, including those that are MDR [12][13][14]. Foremost amongst these are its lipophilicity and low-level resistance profile, as well as recently described inhibitory activity against mycobacterial persisters [15][16][17][18].…”