Mechanisms of action and therapeutic efficacies of the lipophilic antimycobacterial agents clofazimine and bedaquiline

Abstract

Drug-resistant (DR)-TB is the major challenge confronting the global TB control programme, necessitating treatment with second-line anti-TB drugs, often with limited therapeutic efficacy. This scenario has resulted in the inclusion of Group 5 antibiotics in various therapeutic regimens, two of which promise to impact significantly on the outcome of the therapy of DR-TB. These are the 're-purposed' riminophenazine, clofazimine, and the recently approved diarylquinoline, bedaquiline. Although they differ structurally, both of these lipophilic agents possess cationic amphiphilic properties that enable them to target and inactivate essential ion transporters in the outer membrane of Mycobacterium tuberculosis. In the case of bedaquiline, the primary target is the key respiratory chain enzyme F/F-ATPase, whereas clofazimine is less selective, apparently inhibiting several targets, which may underpin the extremely low level of resistance to this agent. This review is focused on similarities and differences between clofazimine and bedaquiline, specifically in respect of molecular mechanisms of antimycobacterial action, targeting of quiescent and metabolically active organisms, therapeutic efficacy in the clinical setting of DR-TB, resistance mechanisms, pharmacodynamics, pharmacokinetics and adverse events.

Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations

“…4B). Clofazimine, previously shown to have potent activity against nonreplicating Mtb in anaerobic conditions (28,29), led to ∼1 log 10 killing at both 5.5 and 10 μM. There was a small (mean, 0.29 log 10 ), statistically significant difference between MPN and cfu enumeration at 5.5 μM of clofazimine.…”

Clofazimine in Nontuberculous Mycobacterial Infections: A Growing Niche

“…It is active against both slowly growing and rapidly growing mycobacteria and most Gram-positive bacteria in vitro [21, 24]. The exact mechanism(s) of antimicrobial action have yet to be fully elucidated, although the cell membrane seems to be the primary site of action [21].…”

“…The exact mechanism(s) of antimicrobial action have yet to be fully elucidated, although the cell membrane seems to be the primary site of action [21]. One putative mechanism of action theorizes that the molecule stimulates phospholipase A 2 activity, resulting in an accumulation of detergent-like lipophospholipids and thus disrupting fundamental cellular functions [21, 24, 25]. It is also proposed that clofazimine may disrupt cell membranes via interaction with intracellular redox cycling, leading to the generation of antimicrobial reactive oxygen species [21, 25].…”

“…Clofazimine is metabolized by glucoronidation in the liver, partially excreted via the bile, and only minimally excreted in the urine, sputum, sebum, and sweat [25, 27, 28]. It does not cross the blood-brain barrier but does cross the placenta and is excreted in breast milk [21, 24, 25, 27, 28]. It is Pregnancy Category C, but there is a paucity of reports of use for multidrug-resistant tuberculosis (MDR-TB) in pregnancy, and scant data exist for later life teratogenicity [27–31].…”

Macrophage-Mediated Clofazimine Sequestration Is Accompanied by a Shift in Host Energy Metabolism

“…27–29 Moreover, the identification of host metabolic changes could enhance the mechanistic understanding of the macrophage-mediated drug sequestration response. 30 …”