Preclinical Study on Novel Treatment Regimen for Elderly Patients with Drug-Sensitive Pulmonary Tuberculosis
- 1Department of Tuberculosis, Shanghai Clinical Research Center for Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai Key Lab of Tuberculosis, Shanghai 200433, China
- 2Institute for Personalized Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
- 3Key Laboratory of Clinical Pharmacology of Antibiotics, National Health Commission of the People’s Republic of China, Institute of Antibiotics, National Clinical Research Centre for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
Abstract
Treatment for elderly patients with pulmonary tuberculosis (PTB) is challenging due to poor efficacy and tolerance. The aim of this study is to preliminarily screen candidate regimens for elderly patients with drug-sensitive PTB. Candidate regimens were initially screened using the artificial-intelligence-enabled phenotypic response surface (AI-PRS) platform and in vitro experiments. The hepatorenal cytotoxicity of drug combinations was assessed with HEK293T and THLE-2 cells. In the in vivo validation stage, aged mice with airway Mycobacterium tuberculosis (Mtb) infection received the novel regimens by oral gavage for 4 weeks, while isoniazid (H)/rifampicin (R)/ethambutol (E)/pyrazinamide (Z) served as the standard regimen control. Hepatorenal function was monitored during the treatment to assess drug safety, and pathological HE staining was also performed to evaluate liver and kidney damage. Bacterial loads in the lungs and spleens were evaluated using colony-forming unit (CFU) assays. After three rounds of AI-PRS analysis and MIC screening in vitro, three optimized treatment regimens were identified including delamanid (Dlm)/bedaquiline (Bdq)/pretomanid (Pa) combined with rifapentine (Rpt), pasiniazid (PAS-H) and levofloxacin (Lfx). After validation with an experiment on aged mice, the Bdq-containing regimen resulted in the mildest pulmonary inflammation and the lowest bacterial loads in lungs and spleens. The bacterial burden was similar between Bdq- and Dlm-containing regimens, which presented stronger bactericidal activity over the HREZ regimen. Regarding drug safety evaluation, the Bdq-containing regimen showed no marked hepatotoxicity and nephrotoxicity in our preclinical models, while other regimens showed variable abnormalities in serum biochemical indices. The Bdq/Lfx/PAS-H/Rpt regimen presented high efficacy and more favorable safety in aged mice compared with the standard regimen, considered as a promising preclinical candidate for elderly patients with drug-sensitive TB and deserving of further clinical trials for evaluation.
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BibTeX
@article{zhou2026preclinical,
title = {{Preclinical Study on Novel Treatment Regimen for Elderly Patients with Drug-Sensitive Pulmonary Tuberculosis}},
author = {Jie Zhou and Bo-Qian Wang and Yu-Jie Zhang and Jie Wang and Wen-Wen Sun and Xiao-Fen Liu and Xian-Ting Ding and Lin Fan},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219848},
url = {https://www.mdpi.com/1422-0067/27/21/9848},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Preclinical Study on Novel Treatment Regimen for Elderly Patients with Drug-Sensitive Pulmonary Tuberculosis
AU - Jie Zhou
AU - Bo-Qian Wang
AU - Yu-Jie Zhang
AU - Jie Wang
AU - Wen-Wen Sun
AU - Xiao-Fen Liu
AU - Xian-Ting Ding
AU - Lin Fan
PY - 2026
DA - 2026/11/03
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219848
UR - https://www.mdpi.com/1422-0067/27/21/9848
AB - Treatment for elderly patients with pulmonary tuberculosis (PTB) is challenging due to poor efficacy and tolerance. The aim of this study is to preliminarily screen candidate regimens for elderly patients with drug-sensitive PTB. Candidate regimens were initially screened using the artificial-intelligence-enabled phenotypic response surface (AI-PRS) platform and in vitro experiments. The hepatorenal cytotoxicity of drug combinations was assessed with HEK293T and THLE-2 cells. In the in vivo validation stage, aged mice with airway Mycobacterium tuberculosis (Mtb) infection received the novel regimens by oral gavage for 4 weeks, while isoniazid (H)/rifampicin (R)/ethambutol (E)/pyrazinamide (Z) served as the standard regimen control. Hepatorenal function was monitored during the treatment to assess drug safety, and pathological HE staining was also performed to evaluate liver and kidney damage. Bacterial loads in the lungs and spleens were evaluated using colony-forming unit (CFU) assays. After three rounds of AI-PRS analysis and MIC screening in vitro, three optimized treatment regimens were identified including delamanid (Dlm)/bedaquiline (Bdq)/pretomanid (Pa) combined with rifapentine (Rpt), pasiniazid (PAS-H) and levofloxacin (Lfx). After validation with an experiment on aged mice, the Bdq-containing regimen resulted in the mildest pulmonary inflammation and the lowest bacterial loads in lungs and spleens. The bacterial burden was similar between Bdq- and Dlm-containing regimens, which presented stronger bactericidal activity over the HREZ regimen. Regarding drug safety evaluation, the Bdq-containing regimen showed no marked hepatotoxicity and nephrotoxicity in our preclinical models, while other regimens showed variable abnormalities in serum biochemical indices. The Bdq/Lfx/PAS-H/Rpt regimen presented high efficacy and more favorable safety in aged mice compared with the standard regimen, considered as a promising preclinical candidate for elderly patients with drug-sensitive TB and deserving of further clinical trials for evaluation.
SN - 1422-0067
ER -