Drug permeation and metabolism in Mycobacterium tuberculosis: Prioritising local exposure as essential criterion in new TB drug development

Abstract

Anti-tuberculosis (TB) drugs possess diverse abilities to penetrate the different host tissues and cell types in which infecting Mycobacterium tuberculosis bacilli are located during active disease. This is important since there is increasing evidence that the respective "lesion-penetrating" properties of the front-line TB drugs appear to correlate well with their specific activity in standard combination therapy. In turn, these observations suggest that rational efforts to discover novel treatment-shortening drugs and drug combinations should incorporate knowledge about the comparative abilities of both existing and experimental anti-TB agents to access bacilli in defined physiological states at different sites of infection, as well as avoid elimination by efflux or inactivation by host or bacterial metabolism. However, while there is a fundamental requirement to understand the mode of action and pharmacological properties of any current or experimental anti-TB agent within the context of the obligate human host, this is complex and, until recently, has been severely limited by the available methodologies and models. Here, we discuss advances in analytical models and technologies which have enabled investigations of drug metabolism and pharmacokinetics (DMPK) for new TB drug development. In particular, we consider the potential to shift the focus of traditional pharmacokinetic-pharmacodynamic analyses away from plasma to a more specific "site of action" drug exposure as an essential criterion for drug development and the design of dosing strategies. Moreover, in summarising approaches to determine DMPK data for the "unit of infection" comprising host macrophage and intracellular bacillus, we evaluate the potential benefits of including these analyses at an early stage in the preclinical drug development algorithm. © 2018 IUBMB Life, 70(9):926-937, 2018.

High-resolution mapping of fluoroquinolones in TB rabbit lesions reveals specific distribution in immune cell types

“…Efficacy and drug distribution studies in animal models of TB disease have shown that reaching adequate drug concentrations at the sites of infection is critical in achieving sterilization and clinical utility ( Irwin et al, 2014 ; Irwin et al, 2016 ; Prideaux et al, 2015a ; Tanner et al, 2018 ; Zimmerman et al, 2017 ). Using analytical approaches and MALDI mass spectrometry imaging (MSI), we previously showed that most TB drugs exhibit differential partitioning between the cellular and necrotic regions of pulmonary lesions ( Irwin et al, 2016 ; Prideaux et al, 2015a ; Zimmerman et al, 2017 ; Prideaux et al, 2011 ; Prideaux et al, 2015b ).…”

In Vitro Efficacies, ADME, and Pharmacokinetic Properties of Phenoxazine Derivatives Active against Mycobacterium tuberculosis

“…The various in vitro efficacy models used in this study allowed the identification of promising compounds for further development, in place of an in vivo efficacy model. Early identification of compounds with high apparent volume of distribution (V) or t 1/2 values is essential to developing targeted drugs that are able to penetrate into the complex granuloma environment (26,47,48). The moderate in vivo t 1/2 of PhX1 was well predicted by the in vitro data generated from human and mouse microsomal incubations.…”

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

“…Although PhX1 seemed to accumulate significantly within the lungs and heart, the total concentration of both compounds was significantly below the MIC 90 level of 0.196 µM for PhX1 and 1.61 µM for RMB041 ( Figures 6 and 7). It is important to develop an understanding of how the compound may behave at the target site of pulmonary TB (Tanner et al, 2018). The estimated organ free fraction concentration values for PhX1 and RMB041 were below the MIC 90 values for both compounds (Figures 6 and 7).…”

“…Thus, it is argued that better predictions for efficacy of a compound against Mtb in vivo would be obtained by determining specific drug concentrations at the target organ (Müller et al, 2004;Tanner et al, 2018). Thus, studies assessing drug concentration in target organs are necessary, preferably at an early stage in the drug discovery process.…”