In vitro pharmacokinetics and pharmacodynamics of the diarylquinoline TBAJ-587 and its metabolites against Mycobacterium tuberculosis

Abstract

The first-in-class diarylquinoline (DARQ) bedaquiline (BDQ) is in the medicines list for drug-resistant tuberculosis. TBAJ-587 is a next-generation DARQ with improved anti-Mycobacterium tuberculosis (Mtb) activity and reduced cardiac repolarization abnormalities. Methods. The in-vitro efficacy of TBAJ-587 and its main metabolites (M2, M3 and M12) was analyzed under standard (ST) growth conditions, with cholesterol (CHO), or fatty acids (FA) as alternative carbon sources. Minimal inhibitory concentration (MIC) assays and time-kill assays (TKA) linked to drug measurements in bacterial samples were performed to allow correlation of pharmacodynamics (PD) with actual pharmacokinetics (PK). The most active compounds, TBAJ-587 and its M3 metabolite, exhibited broth media and concentration dependent efficacy showing a bactericidal effect at [≥]5x MIC. Bacterial cultures treated with 1x MIC and 2x MIC of TBAJ-587 resumed growth after 28 days and displayed moderate increased MIC values compared to untreated conditions, which were linked to new variants of BDQ resistance mutations in the atpE, atpB, and Rv0678 genes. This study revealed TBAJ-587 and metabolites bind to polystyrene plastic-ware, the most commonly used material in antimicrobial research, being the effective unbound drug concentration dependent on the media composition. PKPD analyses determined that Mtb was killed with lower exposures of TBAJ-587 and M3 than expected in ST and FA broth, suggesting previously underestimated potency in these media. This is the first in-vitro study to precisely link compound activities (PD) to their effective concentration (PK) over time in Mtb cultures, providing improved longitudinal data to feed models for translational research.