Inhaled Spectinamide 1599 Combined with Bedaquiline and Pretomanid Shows Equivalent Efficacy to Linezolid-Containing Regimen for Tuberculosis Treatment while Avoiding Linezolid-Associated Adverse Effects

Core Concepts

Inhaled spectinamide 1599 combined with bedaquiline and pretomanid (BPaS regimen) has similar efficacy to the BPaL regimen (bedaquiline, pretomanid, linezolid) in murine tuberculosis models, but avoids the linezolid-associated adverse effects.

Abstract

The content evaluates a modified BPaL regimen for tuberculosis (TB) treatment, where linezolid (L) is replaced with inhaled spectinamide 1599 (S) in combination with bedaquiline (B) and pretomanid (Pa) (BPaS regimen). The key highlights are: Both BPaL and BPaS regimens showed equivalent bactericidal effects in Balb/c and C3HeB/FeJ chronic TB mouse models. However, the BPaL regimen was associated with significant weight loss and hematological changes indicative of anemia, which were not observed with the BPaS regimen. Bone marrow analysis revealed that the BPaL regimen decreased the myeloid to erythroid ratio and increased proinflammatory cytokines compared to the BPaS regimen. Both BPaL and BPaS therapies improved lung lesion burden, reduced inflammatory cells, and increased adaptive immune cells in the lungs. These results suggest that the BPaS regimen maintains the efficacy of the BPaL regimen while avoiding the linezolid-associated adverse effects.

Stats

The content does not provide specific numerical data to support the key logics. However, it presents the following important figures: BPaL and BPaS regimens reduced lung bacterial burden by 3.8-4.0 log10 and 2.5-2.7 log10 in Balb/c and C3HeB/FeJ TB models, respectively, compared to untreated controls. BPaL treatment resulted in a significant decrease in hemoglobin concentration and increase in red blood cell distribution width, indicative of anemia, which was not observed with BPaS treatment. BPaL treatment decreased the myeloid to erythroid ratio in bone marrow, while BPaS treatment did not alter this ratio compared to untreated controls.

Quotes

The content does not contain any direct quotes that support the key logics.

Key Insights Distilled From

A Modified BPaL Regimen for Tuberculosis Treatment replaces Linezolid with Inhaled Spectinamides

by Zohaib Ali,M... at www.biorxiv.org 11-16-2023

https://www.biorxiv.org/content/10.1101/2023.11.16.567434v1

Deeper Inquiries

What are the potential mechanisms by which spectinamide 1599 avoids the adverse effects associated with linezolid in the BPaL regimen

Spectinamide 1599 avoids the adverse effects associated with linezolid in the BPaL regimen through several potential mechanisms. Firstly, spectinamide 1599 is a protein synthesis inhibitor of Mycobacterium tuberculosis with a high safety profile, lacking the mitochondrial toxicity associated with linezolid. Linezolid binds to host mitochondrial ribosomes, leading to mitochondrial toxicities and subsequent myelosuppression, which is a common adverse effect of long-term linezolid administration. In contrast, spectinamide 1599 does not bind to mitochondrial ribosomes, reducing the potential for side effects related to mitochondrial toxicity. This difference in binding targets contributes to the improved safety profile of spectinamide 1599 compared to linezolid. Additionally, spectinamide 1599 has shown excellent activity against multidrug-resistant and extensively drug-resistant Mtb strains without the associated toxicities seen with linezolid, making it a promising alternative in the BPaS regimen.

How do the lung lesion characteristics and immune cell profiles differ between the BPaL and BPaS regimens, and what are the implications for long-term treatment outcomes

The lung lesion characteristics and immune cell profiles differ between the BPaL and BPaS regimens, with implications for long-term treatment outcomes. In terms of lung lesions, both regimens showed a significant reduction in the number and size of TB granulomas in both the C3HeB/FeJ and Balb/c TB models. However, the BPaL regimen was associated with a significant decrease in live body weight, indicative of potential adverse effects, while the BPaS regimen did not show similar effects. This suggests that the BPaS regimen may have a more favorable safety profile compared to BPaL, making it a potentially safer option for long-term treatment. In terms of immune cell profiles, the BPaL and BPaS regimens had different effects on inflammatory myeloid cells, neutrophils, precursor T cells, B cells, and other immune cell populations in the bone marrow, blood, and lungs. The BPaS regimen showed a reduction in inflammatory myeloid cells and neutrophils, along with an increase in helper T cells, regulatory T cells, and B cells in the lungs. These changes indicate a shift towards a more balanced immune response with the BPaS regimen, which may contribute to improved treatment outcomes and reduced inflammation compared to the BPaL regimen.

Given the promising preclinical results, what are the next steps in the clinical development of the BPaS regimen for tuberculosis treatment

Given the promising preclinical results of the BPaS regimen for tuberculosis treatment, the next steps in its clinical development would involve further evaluation in clinical trials. These trials would aim to assess the safety, efficacy, and tolerability of the BPaS regimen in human patients with multidrug-resistant and extensively drug-resistant TB. Key aspects of the clinical development process would include dose optimization, pharmacokinetic studies, and monitoring of treatment outcomes in a diverse patient population. Additionally, long-term follow-up studies would be essential to evaluate the durability of treatment response, the development of resistance, and any potential long-term adverse effects associated with the BPaS regimen. Collaborations with regulatory agencies, healthcare providers, and TB treatment programs would be crucial to ensure the successful clinical development and eventual implementation of the BPaS regimen as a novel treatment option for TB.