---
title: "Preclinical study finds lesional liability for PaBQU and DBQU regimens in hard-to-treat TB models"
id: "biorxiv-14-comprehensive-preclinical-reevaluation-of-pabqu-and-dbqu-regimens-identifies"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-14-comprehensive-preclinical-reevaluation-of-pabqu-and-dbqu-regimens-identifies"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.15.751879v1?rss=1"
published_at: "2026-09-17T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Preclinical study finds lesional liability for PaBQU and DBQU regimens in hard-to-treat TB models
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-14-comprehensive-preclinical-reevaluation-of-pabqu-and-dbqu-regimens-identifies
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.15.751879v1?rss=1)
- **Published At:** 2026-09-17T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- A recent human Phase 2 trial testing 4-month **PaBQU** and **DBQU** regimens was terminated early because neither regimen met the Target Regimen Profile for treatment shortening (≤ 3 months). The authors examined whether lesional liability could explain the clinical outcome. - The study performed a translational preclinical comparison between an easy-to-treat mouse model (BALB/c) that lacks complex lesions and a hard-to-treat mouse model (C3HeB/FeJ) that develops complex, human-like lung lesions. - Pharmacodynamic measures included traditional colony forming units (**CFU**) and a novel **RS ratio** marker; outcomes also included relapse rates and ex vivo **caseum** pharmacokinetics for regimen drugs. - Both **PaBQU** and **DBQU** were slower to produce bactericidal effects, to change **RS ratio** activity, and to prevent relapse in the C3HeB/FeJ model than in BALB/c mice, indicating lesional liability in complex lesions. - A reference regimen, **BPaMZ**, demonstrated less lesional liability than PaBQU and DBQU in these preclinical comparisons. - Pharmacokinetic projections indicated fewer drugs in the **PaBQU** regimens were expected to achieve target attainment in **caseum** compared with **BPaMZ**, notably early in treatment; slow accumulation of **bedaquiline** in caseum was identified as a contributing factor. - The authors applied a multi-modality pharmacokinetic–pharmacodynamic analysis to compare regimen activity across models, demonstrating the potential value of assaying lesional drug exposure and activity when predicting clinical treatment-shortening potential. - The study concludes that systematic interrogation of additional and diverse regimens is needed to determine whether preclinical measures of lesional liability can reliably predict clinical treatment shortening outcomes.
## Clinical Analysis & Structured Key Points
Comprehensive preclinical reevaluation of PaBQU and DBQU regimens identifies lesional liability in hard-to-treat forms of tuberculosis | bioRxiv Skip to main content New Results Comprehensive preclinical reevaluation of PaBQU and DBQU regimens identifies lesional liability in hard-to-treat forms of tuberculosis Nicholas D Walter , Lisa M Massoudi , Allison A Bauman , Noalani D Benedict , Nathan Peroutka-Bigus , Michelle E Ramey , Reem Al Mubarak , Samantha Pauly , Firat Kaya , Linda Chaba , Matthew D Zimmerman , Debra Flood , David Hermann , Khisimusi Mdluli , David Holtzman , Radojka Savic , Jansy P Sarathy , Gregory T Robertson doi: https://doi.org/10.64898/2026.09.15.751879 Nicholas D Walter 1 University of Colorado Anschutz Medical Campus; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lisa M Massoudi 2 Colorado State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Allison A Bauman 2 Colorado State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Noalani D Benedict 2 Colorado State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nathan Peroutka-Bigus 2 Colorado State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michelle E Ramey 2 Colorado State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Reem Al Mubarak 1 University of Colorado Anschutz Medical Campus; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Samantha Pauly 1 University of Colorado Anschutz Medical Campus; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Firat Kaya 3 Hackensack Meridian Health; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Linda Chaba 4 University of California San Francisco, San Francisco; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Matthew D Zimmerman 3 Hackensack Meridian Health; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Debra Flood 5 Gates Foundation; Find this author on Google Scholar Find this author on PubMed Search for this author on this site David Hermann 5 Gates Foundation; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Khisimusi Mdluli 6 Gates Medical Research Institute Find this author on Google Scholar Find this author on PubMed Search for this author on this site David Holtzman 6 Gates Medical Research Institute Find this author on Google Scholar Find this author on PubMed Search for this author on this site Radojka Savic 4 University of California San Francisco, San Francisco; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jansy P Sarathy 3 Hackensack Meridian Health; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Gregory T Robertson 2 Colorado State University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: gregory.robertson{at}colostate.edu Abstract Info/History Metrics Supplementary material Preview PDF Abstract Murine efficacy models inform advancement of preclinical tuberculosis treatment regimens to human clinical testing. A recent human Phase 2 trial was terminated early because investigational regimens (4-months of PaBQU or DBQU) did not meet the treatment shortening criteria outlined in the Target Regimen Profile (≤ 3 months). We queried whether a factor leading to this early termination may have been lesional liability, meaning slow or diminished onset of effect in the caseum of complex lung lesions. We conducted a translational study, comparing the easy-to-treat BALB/c mouse, lacking complex lesions, to the hard-to-treat C3HeB/FeJ mouse that develops complex human-like lesions. We evaluated traditional and novel pharmacodynamic markers (colony forming units and RS ratio), relapse outcomes and ex vivo caseum pharmacokinetics. PaBQU and DBQU were slower to elicit bactericidal activity, RS ratio activity and prevent relapse in the C3HeB/FeJ mouse than the BALB/c mouse. A reference regimen (BPaMZ) had less lesional liability than PaBQU and DBQU. Fewer drugs in PaBQU were projected to achieve target attainment in caseum compared to BPaMZ, particularly early in treatment due to slow accumulation of bedaquiline in caseum. Here, we demonstrated application of a multi-modality pharmacokinetic-pharmacodynamic analysis that compared regimen activity in the hard-to-treat C3HeB/FeJ and easy-to-treat BALB/c mouse models, identifying lesional liability of PaBQU and DBQU. Systematic interrogation of additional diverse regimens is needed to determine the value of preclinical lesional liability as a means of predicting clinical treatment shortening activity. Competing Interest Statement The authors have declared no competing interest. Funder Information Declared Gates Foundation, https://ror.org/0456r8d26 , INV-009105 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted September 17, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Comprehensive preclinical reevaluation of PaBQU and DBQU regimens identifies lesional liability in hard-to-treat forms of tuberculosis Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Comprehensive preclinical reevaluation of PaBQU and DBQU regimens identifies lesional liability in hard-to-treat forms of tuberculosis Nicholas D Walter , Lisa M Massoudi , Allison A Bauman , Noalani D Benedict , Nathan Peroutka-Bigus , Michelle E Ramey , Reem Al Mubarak , Samantha Pauly , Firat Kaya , Linda Chaba , Matthew D Zimmerman , Debra Flood , David Hermann , Khisimusi Mdluli , David Holtzman , Radojka Savic , Jansy P Sarathy , Gregory T Robertson bioRxiv 2026.09.15.751879; doi: https://doi.org/10.64898/2026.09.15.751879 Share This Article: Copy Citation Tools Comprehensive preclinical reevaluation of PaBQU and DBQU regimens identifies lesional liability in hard-to-treat forms of tuberculosis Nicholas D Walter , Lisa M Massoudi , Allison A Bauman , Noalani D Benedict , Nathan Peroutka-Bigus , Michelle E Ramey , Reem Al Mubarak , Samantha Pauly , Firat Kaya , Linda Chaba , Matthew D Zimmerman , Debra Flood , David Hermann , Khisimusi Mdluli , David Holtzman , Radojka Savic , Jansy P Sarathy , Gregory T Robertson bioRxiv 2026.09.15.751879; doi: https://doi.org/10.64898/2026.09.15.751879 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (8007) Biochemistry (18718) Bioengineering (14855) Bioinformatics (44378) Biophysics (22570) Cancer Biology (19698) Cell Biology (26874) Clinical Trials (138) Developmental Biology (13952) Ecology (20986) Epidemiology (2067) Evolutionary Biology (25435) Genetics (16158) Genomics (23493) Immunology (18687) Microbiology (42434) Molecular Biology (18041) Neuroscience (93380) Paleontology (700) Pathology (2977) Pharmacology and Toxicology (5087) Physiology (8109) Plant Biology (15985) Scientific Communication and Education (2095) Synthetic Biology (4556) Systems Biology (10226) Zoology (2386)
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