Frontiers in microbiology · 2026
In vitro pharmacokinetics and pharmacodynamics of the diarylquinoline TBAJ-587 and its metabolites against Mycobacterium tuberculosis.
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Aguilar-Ayala Diana Angelica, Rabodoarivelo Marie Sylvianne, Eveque-Mourroux Maxime R, Leding Albin A M, Sonnenkalb Lindsay, Picó Marco Ana, Willand Nicolas, Serbina Natalya, Simonsson Ulrika S H, Lucía Ainhoa, Ramón-García Santiago
Аннотация
INTRODUCTION: 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 and with cholesterol (CHO), or fatty acids (FA) as physiologically relevant 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 in vitro pharmacokinetics (PK).
RESULTS: 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 that TBAJ-587 and its 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.
DISCUSSION: Unlike commonly performed in in vitro PKPD studies that solely rely on nominal drug concentrations, our work precisely relates compound activity to actual effective concentrations that are measured over time directly in Mtb cultures, providing improved longitudinal data to feed in silico models for translational research.
METHODS: The in vitro efficacy of TBAJ-587 and its main metabolites (M2, M3 and M12) was analyzed under standard (ST) growth conditions and with cholesterol (CHO), or fatty acids (FA) as physiologically relevant 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 in vitro pharmacokinetics (PK).
RESULTS: 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 that TBAJ-587 and its 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.
DISCUSSION: Unlike commonly performed in in vitro PKPD studies that solely rely on nominal drug concentrations, our work precisely relates compound activity to actual effective concentrations that are measured over time directly in Mtb cultures, providing improved longitudinal data to feed in silico models for translational research.