Combination of Mycobacterium tuberculosis RS Ratio and CFU Improves the Ability of Murine Efficacy Experiments to Distinguish between Drug Treatments

Dide-Agossou, Christian; Bauman, Allison; Ramey, Michelle E.; Rossmassler, Karen; Mubarak, Reem Al; Pauly, Samantha; Voskuil, Martin I.; Garcia‐Cremades, Maria; Savic, Radojka M.; Nahid, Payam; Moore, Camille M.; Tasneen, Rokeya; Nuermberger, Eric; Robertson, Gregory T.; Walter, Nicholas D.

doi:10.1128/aac.02310-21

Cited by 17 publications

(14 citation statements)

References 22 publications

(31 reference statements)

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“…For example, regimens that have identical effects on CFU in mice can have different long-term relapse outcomes. 10,74 In previous studies, we demonstrated that quantification of rRNA synthesis via the RS ratio showed proof of concept that molecular measures of bacterial cellular processes in vivo can distinguish regimens that are indistinguishable based on CFU. 10,74 SEARCH-TB advances molecular characterization of drug effects in vivo to a higher level of granularity.…”

Section: Discussionmentioning

confidence: 87%

“…10,74 In previous studies, we demonstrated that quantification of rRNA synthesis via the RS ratio showed proof of concept that molecular measures of bacterial cellular processes in vivo can distinguish regimens that are indistinguishable based on CFU. 10,74 SEARCH-TB advances molecular characterization of drug effects in vivo to a higher level of granularity. Others have demonstrated the power of Mtb transcriptional readouts of drug effect to predict drug interactions in vitro.…”

Section: Discussionmentioning

confidence: 87%

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Transcriptional adaptation of drug-tolerantMycobacterium tuberculosisin mice

Wynn

Dide-Agossou²,

Reichlen

et al. 2023

Preprint

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Transcriptome evaluation ofMycobacterium tuberculosisin the lungs of laboratory animals during long-term treatment has been limited by extremely low abundance of bacterial mRNA relative to eukaryotic RNA. Here we report a targeted amplification RNA sequencing method called SEARCH-TB. After confirming that SEARCH-TB recapitulates conventional RNA-seqin vitro, we applied SEARCH-TB toMycobacterium tuberculosis-infected BALB/c mice treated for up to 28 days with the global standard isoniazid, rifampin, pyrazinamide, and ethambutol regimen. We compared results in mice with 8-day exposure to the same regimenin vitro. After treatment of mice for 28 days, SEARCH-TB suggested broad suppression of genes associated with bacterial growth, transcription, translation, synthesis of rRNA proteins and immunogenic secretory peptides. Adaptation of drug-stressedMycobacterium tuberculosisappeared to include a metabolic transition from ATP-maximizing respiration towards lower-efficiency pathways, modification and recycling of cell wall components, large-scale regulatory reprogramming, and reconfiguration of efflux pumps expression. Despite markedly different expression at pre-treatment baseline, murine andin vitrosamples had broadly similar transcriptional change during treatment. The differences observed likely indicate the importance of immunity and pharmacokinetics in the mouse. By elucidating the long-term effect of tuberculosis treatment on bacterial cellular processesin vivo, SEARCH-TB represents a highly granular pharmacodynamic monitoring tool with potential to enhance evaluation of new regimens and thereby accelerate progress towards a new generation of more effective tuberculosis treatment.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 87%

Transcriptional adaptation of drug-tolerantMycobacterium tuberculosisin mice

Wynn

Dide-Agossou²,

Reichlen

et al. 2023

Preprint

Self Cite

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“…The EBA of rifampicin was evaluated using all available CFU and TTP data simultaneously, which further supported a strong mechanistic approach when developing the work and assessing the drug efficacy. Studies have shown that the combined use of two biomarkers better ranked the efficacy between treatments compared to using only one biomarker, as in the case of the combined use of CFU and RS ratio ( Dide-agossou et al, 2022 ). Liquid media are known to be more sensitive in detecting the Mtb populations than solid media but are more prone to contamination ( Cruciani et al, 2004 ; Diacon et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Combined quantitative tuberculosis biomarker model for time-to-positivity and colony forming unit to support tuberculosis drug development

Alsoud

Svensson²,

Svensson³

et al. 2023

Front. Pharmacol.

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Biomarkers are quantifiable characteristics of biological processes. In Mycobacterium tuberculosis, common biomarkers used in clinical drug development are colony forming unit (CFU) and time-to-positivity (TTP) from sputum samples. This analysis aimed to develop a combined quantitative tuberculosis biomarker model for CFU and TTP biomarkers for assessing drug efficacy in early bactericidal activity studies. Daily CFU and TTP observations in 83 previously patients with uncomplicated pulmonary tuberculosis after 7 days of different rifampicin monotherapy treatments (10–40 mg/kg) from the HIGHRIF1 study were included in this analysis. The combined quantitative tuberculosis biomarker model employed the Multistate Tuberculosis Pharmacometric model linked to a rifampicin pharmacokinetic model in order to determine drug exposure-response relationships on three bacterial sub-states using both the CFU and TTP data simultaneously. CFU was predicted from the MTP model and TTP was predicted through a time-to-event approach from the TTP model, which was linked to the MTP model through the transfer of all bacterial sub-states in the MTP model to a one bacterial TTP model. The non-linear CFU-TTP relationship over time was well predicted by the final model. The combined quantitative tuberculosis biomarker model provides an efficient approach for assessing drug efficacy informed by both CFU and TTP data in early bactericidal activity studies and to describe the relationship between CFU and TTP over time.

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“…Separate from investigation of it’s predictive capacity, the Isserlis formula provided a deconstruction of the PD effects of BPaL as a sum of effects arising from single-drug and pairwise products. The PD effects were also characterized for each drug component by a kill rate constant for bactericidal activity, and RS ratio half-life and equilibration as a measure of rRNA synthesis (16, 25). The interactions were quantified over time as deviations from Bliss and Isserlis formulas, with the latter including mutual interactions in contrast to the former which did not.…”

Section: Discussionmentioning

confidence: 99%

Use of Multiple Pharmacodynamic Measures to Deconstruct the Nix-TB Regimen in a Short-Course Murine Model of Tuberculosis

Lyons,

Obregon-Henao,

Ramey

et al. 2023

Preprint

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A major challenge for tuberculosis (TB) drug development is to prioritize promising combination regimens from a large and growing number of possibilities. This includes demonstrating individual drug contributions to the activity of higher-order combinations. A BALB/c mouse TB infection model was used to evaluate the contributions of each drug and pairwise combination in the clinically relevant Nix-TB regimen (bedaquiline-pretomanid-linezolid [BPaL]) during the first three weeks of treatment at human equivalent doses. RS ratio, an exploratory pharmacodynamic (PD) marker of ongoingMycobacterium tuberculosisrRNA synthesis, to-gether with solid culture CFU and liquid culture time to positivity (TTP) were used as PD markers of treatment response in lung tissue; and their time course profiles were mathematically modeled using rate equations with pharmacologically interpretable parameters. Antimicrobial interactions were quantified using Bliss independence and Isserlis formulas. Subadditive (or antagonistic) and additive effects on bacillary load, assessed by CFU and TTP, were found for bedaquiline-pretomanid and linezolid-containing pairs, respectively. In contrast, subadditive and additive effects on rRNA synthesis were found for pretomanid-linezolid and bedaquiline-containing pairs, respectively. Additionally, accurate predictions of the response to BPaL for all three PD markers were made using only the single-drug and pairwise effects together with an assumption of negligible three-way drug interactions. The results represent an experimental and PD modeling approach aimed at reducing combinatorial complexity and improving the cost-effectiveness ofin vivosystems for preclinical TB regimen development.

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Combination of Mycobacterium tuberculosis RS Ratio and CFU Improves the Ability of Murine Efficacy Experiments to Distinguish between Drug Treatments

Cited by 17 publications

References 22 publications

Transcriptional adaptation of drug-tolerantMycobacterium tuberculosisin mice

Transcriptional adaptation of drug-tolerantMycobacterium tuberculosisin mice

Combined quantitative tuberculosis biomarker model for time-to-positivity and colony forming unit to support tuberculosis drug development

Use of Multiple Pharmacodynamic Measures to Deconstruct the Nix-TB Regimen in a Short-Course Murine Model of Tuberculosis

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