New TB drug TBAJ-587 shows unexpected potency, but lab tests may mislead

Tuberculosis research has gained a promising new candidate in the diarylquinoline (DARQ) family. The first-in-class diarylquinoline bedaquiline (BDQ) is already in the medicines list for drug-resistant tuberculosis, and researchers led by Santiago Ramón‐García tested a next-generation DARQ called TBAJ-587. According to the study abstract, TBAJ-587 combines improved anti-Mycobacterium tuberculosis (Mtb) activity with reduced cardiac repolarization abnormalities. To explore how this compound behaves against Mtb in the lab, the team studied TBAJ-587 together with its main metabolites, named M2, M3 and M12. They grew Mtb under three different nutrient scenarios: standard (ST) growth conditions, with cholesterol (CHO), or with fatty acids (FA) as alternative carbon sources. The goal was not only to see whether the drugs killed bacteria but to measure drug levels over time inside samples, so that pharmacodynamics (PD) – what the drug does to the bacteria – could be tied directly to pharmacokinetics (PK) – how much active drug was present. This approach aimed to produce a clearer, time-resolved picture of drug action in Mtb cultures than typical single-point measurements.

The team used Minimal inhibitory concentration (MIC) assays and time-kill assays (TKA) linked to drug measurements in bacterial samples to correlate PD with actual PK. Results showed that the most active compounds were TBAJ-587 and its M3 metabolite. Both exhibited broth media and concentration dependent efficacy, producing a bactericidal effect at concentrations at or above ≥5x MIC. However, when bacterial cultures were treated with 1x MIC and 2x MIC of TBAJ-587 they resumed growth after 28 days and displayed moderately increased MIC values compared to untreated conditions. Those changes in susceptibility were linked to new variants of BDQ resistance mutations in the atpE, atpB, and Rv0678 genes. The study also revealed that TBAJ-587 and metabolites bind to polystyrene plastic-ware, the most commonly used material in antimicrobial research, meaning the effective unbound drug concentration depended on the media composition. PKPD analyses further 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.

These findings carry several practical implications for research and drug development. First, the observation that TBAJ-587 and M3 are more potent than expected in some media suggests standard lab assays may under- or overestimate activity unless drug binding and media effects are accounted for; binding to polystyrene plastic-ware changes the fraction of unbound, active compound and therefore the true exposure experienced by bacteria. Second, the emergence of new variants of BDQ resistance mutations in atpE, atpB, and Rv0678 after extended exposure at lower concentrations highlights the importance of linking concentration over time to bacterial response: suboptimal exposures allowed regrowth and selection of resistance. Third, because TBAJ-587 reportedly has improved anti-Mycobacterium tuberculosis activity and reduced cardiac repolarization abnormalities, these lab results—now the first in-vitro study to precisely link PD to PK over time in Mtb cultures—provide more realistic longitudinal data to feed translational models. In short, the work points to the need for careful PKPD-informed testing when advancing promising compounds such as TBAJ-587 toward clinical development and for adjusting laboratory methods to reflect true effective concentrations.