Biology subjects

Obregon-Henao, A.

Publications and source records attributed to Obregon-Henao, A..

3 recordsLinked to original sources

bioRxiv2025

Deconvoluting drug interactions based on M. tuberculosis physiologic processes:Transcriptional disaggregation of the BPaL regimen in vivo

Identification of optimal antibiotic combination treatments for tuberculosis (TB) in preclinical studies is impeded by the limited information conventional pharmacodynamic (PD) markers provide about drug interactions. Measurement of individual drug activity based on colony forming units (CFU) does not reliably predict the activity of drug combinations, potentially because one drug may affect the physiology of Mycobacterium tuberculosis (Mtb) in a way that either favors or disfavors the activity of a second drug. SEARCH-TB is a novel candidate PD approach which uses targeted in vivo transcriptional profiling to evaluate the effects of drugs on Mtb physiology. To test the capacity of SEARCH-TB to elucidate drug interactions, we deconstructed the BPaL (bedaquiline, pretomanid, linezolid) regimen in the BALB/c high-dose aerosol mouse infection model, measuring the effect of 2, 7, and 14-day treatment with drugs in monotherapy, pairwise combinations, and as a 3-drug combination. Monotherapy rapidly induced drug-specific Mtb transcriptional responses by day 2 with continued evolution over 14 days. Bedaquiline dominated pairwise combinations with both pretomanid and linezolid. The pretomanid-linezolid combination gave a blended response, inducing transcriptional profiles "intermediate" between either drug. In the 3-drug BPaL regimen, the addition of both pretomanid and linezolid to bedaquiline yielded a greater transcriptional response than expected based on pairwise results. This work demonstrates that physiologic perturbations induced by a single drug may be modified in complex ways when drugs are combined. This establishes proof of concept that SEARCH-TB is a highly granular readout of drug interactions in vivo, providing information distinct from CFU burden and suggesting a future in which regimen selection is informed by in vivo molecular measures of Mtb physiology.

genomics↗

bioRxiv2023

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

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 ongoing Mycobacterium tuberculosis rRNA 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 of in vivo systems for preclinical TB regimen development.

pharmacology and toxicology↗

bioRxiv2020

A Whole Virion Vaccine for COVID-19 Produced Via a Novel Inactivation Method: Results from Animal Challenge Model Studies

The COVID-19 pandemic has generated intense interest in the rapid development and evaluation of vaccine candidates for this disease and other emerging diseases. Several novel methods for preparing vaccine candidates are currently undergoing clinical evaluation in response to the urgent need to prevent the spread of COVID-19. In many cases, these methods rely on new approaches for vaccine production and immune stimulation. We report on the use of a novel method (SolaVAX) for production of an inactivated vaccine candidate and the testing of that candidate in a hamster animal model for its ability to prevent infection upon challenge with SARS-CoV-2 virus. The studies employed in this work included an evaluation of the levels of neutralizing antibody produced post-vaccination, levels of specific antibody sub-types to RBD and spike protein that were generated, evaluation of viral shedding post-challenge, flow cytometric and single cell sequencing data on cellular fractions and histopathological evaluation of tissues post-challenge. The results from this study provide insight into the immunological responses occurring as a result of vaccination with the proposed vaccine candidate and the impact that adjuvant formulations, specifically developed to promote Th1 type immune responses, have on vaccine efficacy and protection against infection following challenge with live SARS-CoV-2. This data may have utility in the development of effective vaccine candidates broadly. Furthermore, the results suggest that preparation of a whole virion vaccine for COVID-19 using this specific photochemical method may have utility in the preparation of one such vaccine candidate. Author SummaryWe have developed a vaccine for COVID-19 which is prepared by a novel method for inactivation of a whole virion particle and tested it in a hamster animal model for its ability to protect against SARS-CoV-2 infection.

immunology↗