Accumulation of TB-Active Compounds in Murine Organs Relevant to Infection by Mycobacterium tuberculosis

Abstract

Tuberculosis (TB), the leading cause of death due to an infectious agent, requires prolonged and costly drug treatments. With the rise in incidence of MDR and XDR TB, newer more efficacious treatments which are better able to permeate into the deeper recesses of the human lung where bacteria reside are urgently required. To this end, two new promising drug candidates, the decoquinate derivative RMB041 and the phenoxazine PhX1, were assessed for their abilities to permeate into specific murine organs. In particular, PhX1 permeation into the lungs and heart was notably efficient, as reflected in the high relative AUC values of 9669 ± 120.2 min/nmol/mg and 12450 ± 45.2 min/nmol/mg for lung and heart tissue, respectively. However, neither compound maintained a free concentration in the lung which exceeded the compound's respective MIC 90 values, indicating the importance of correcting for organ specific binding.

Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics

“…Recently, an N-alkyl DQ derivative (RMB041) showed high activity against Mtb (MIC 90 = 1.61 µM), with similar in vitro potency to that of ciprofloxacin (1.5-12 µM), gatifloxacin (0.66-1.3 µM), and moxifloxacin (0.62-1.3 µM) [20]. Its permeability (LogP app = −4.8, where compounds with values > −5 are considered highly permeable [21]) confers a benefit for drug diffusion through the lipid cell wall [22] and penetration of infected macrophages and granulomatous lesions in the lungs [23,24]. This drug also shows low cytotoxicity in human fetal lung fibroblasts [25], as well as promising pharmacokinetic properties, including an intravenous elimination half-life (t 1/2 ) of 62.3 h in murine models and a low human intrinsic clearance rate (CL int ) (16 µL/min/mg) [2].…”

In SilicoDrug Discovery Strategies Identified ADMET Properties of Decoquinate RMB041 and Its Potential Drug Targets against Mycobacterium tuberculosis

“…It may also indicate however, that this compound would likely be of little use for the treatment of TB meningitis. Blood plasma volume of distribution of decoquinate RMB041 (log VDss > 0.32) ( Table 3 ) is on the higher end of the spectrum (log VDss < −0.15 is low; log VDss >0.45 is high), suggesting moderate delivery to infected areas ( 30 , 31 ).…”

Chemical and Pharmacological Properties of Decoquinate: A Review of Its Pharmaceutical Potential and Future Perspectives

“…Moreover, new compounds from DQ have been observed to increase oral bioavailability by up to 20% in mice. The in vivo half-life (t 1/2 ) of the derivative was also found to be medium to long (150 min), which would reduce the cost of current therapies and improve treatment adherence by favoring the shortening and duration of TB treatment [ 17 , 61 , 62 ]. To date, it is unclear whether the in vitro activity of DQ derivatives against Mtb can be translated into effective therapy for TB, as no systematic study of efficacy has been conducted in murine models of TB infection.…”