TY - JOUR
T1 - Relative Contributions of the Novel Diarylquinoline TBAJ-876 and its Active Metabolite to the Bactericidal Activity in a Murine Model of Tuberculosis
AU - Mudde, Saskia E.
AU - Ammerman, Nicole C.
AU - Ten Kate, Marian T.
AU - Fotouhi, Nader
AU - Lotlikar, Manisha U.
AU - Bax, Hannelore I.
AU - De Steenwinkel, Jurriaan E.M.
N1 - Publisher Copyright:
© 2024 The Author(s). Published by Oxford University Press on behalf of Infectious Diseases Society of America.
PY - 2024/12/15
Y1 - 2024/12/15
N2 - Background: TBAJ-876 is a next-generation diarylquinoline. In vivo, diarylquinoline metabolites are formed with activity against Mycobacterium tuberculosis. Species-specific differences in parent drug-To-metabolite ratios might impact the translational value of animal model-based predictions. This study investigates the contribution of TBAJ-876 and its major active metabolite, TBAJ-876-M3 (M3), to the total bactericidal activity in a mouse tuberculosis model. Methods: In vitro activity of TBAJ-876 and M3 was investigated and compared to bedaquiline. Subsequently, a dose-response study was conducted in M.Tuberculosis-infected BALB/c mice treated with TBAJ-876 (1.6/6.3/25 mg/kg) or M3 (3.1/12.5/50 mg/kg). Colony-forming units in the lungs and TBAJ-876 and M3 plasma concentrations were determined. M3's contribution to TBAJ-876's bactericidal activity was estimated based on M3 exposure following TBAJ-876 treatment and corresponding M3 activity observed in M3-Treated animals. Results: TBAJ-876 and M3 demonstrated profound bactericidal activity. Lungs of mice treated for 4 weeks with 50 mg/kg M3 were culture negative. Following TBAJ-876 treatment, M3 exposures were 2.2 to 3.6-fold higher than for TBAJ-876. TBAJ-876 activity was substantially attributable to M3, given its high exposure and potent activity. Conclusions: These findings emphasize the need to consider metabolites and their potentially distinct exposure and activity profiles compared to parent drugs to enhance the translational value of mouse model-driven predictions.
AB - Background: TBAJ-876 is a next-generation diarylquinoline. In vivo, diarylquinoline metabolites are formed with activity against Mycobacterium tuberculosis. Species-specific differences in parent drug-To-metabolite ratios might impact the translational value of animal model-based predictions. This study investigates the contribution of TBAJ-876 and its major active metabolite, TBAJ-876-M3 (M3), to the total bactericidal activity in a mouse tuberculosis model. Methods: In vitro activity of TBAJ-876 and M3 was investigated and compared to bedaquiline. Subsequently, a dose-response study was conducted in M.Tuberculosis-infected BALB/c mice treated with TBAJ-876 (1.6/6.3/25 mg/kg) or M3 (3.1/12.5/50 mg/kg). Colony-forming units in the lungs and TBAJ-876 and M3 plasma concentrations were determined. M3's contribution to TBAJ-876's bactericidal activity was estimated based on M3 exposure following TBAJ-876 treatment and corresponding M3 activity observed in M3-Treated animals. Results: TBAJ-876 and M3 demonstrated profound bactericidal activity. Lungs of mice treated for 4 weeks with 50 mg/kg M3 were culture negative. Following TBAJ-876 treatment, M3 exposures were 2.2 to 3.6-fold higher than for TBAJ-876. TBAJ-876 activity was substantially attributable to M3, given its high exposure and potent activity. Conclusions: These findings emphasize the need to consider metabolites and their potentially distinct exposure and activity profiles compared to parent drugs to enhance the translational value of mouse model-driven predictions.
UR - http://www.scopus.com/inward/record.url?scp=85212682034&partnerID=8YFLogxK
U2 - 10.1093/infdis/jiae332
DO - 10.1093/infdis/jiae332
M3 - Article
C2 - 38941358
AN - SCOPUS:85212682034
SN - 0022-1899
VL - 230
SP - e1366-e1374
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 6
ER -