Biology subjects

Aguilar-Perez, C.

Publications and source records attributed to Aguilar-Perez, C..

3 recordsLinked to original sources

bioRxiv2026

Next Generation TB Drug Combinations from the Pan-TB Consortium: Combination Efficacy and Contributions of Individual Agents, Evaluated in a BALB/c Mouse TB Model

The Project to Accelerate New Treatments for Tuberculosis (PAN-TB) aims to accelerate development of shorter, simpler and safer pan-TB combinations. We previously identified 3 out of 25 first-generation novel PAN-TB 4-drug combinations, that cured 90% of mice in less than 3 months, at clinically relevant doses in the relapsing mouse model of TB. These regimens include BPa830Sut, BPa286Sut and BQSut286 (B: bedaquiline; Pa: pretomanid; 830: GSK3211830; 286: GSK2556286; Sut: sutezolid; Q: quabodepistat). Here, we assess the efficacy of these combinations where the original candidates are substituted next-generation or more advanced compounds (ganfeborole (656) for 830, sorfequiline, S for B, TBD09 for Sut and TBD11 for 286) and the individual contributions of specific agents. Six novel regimens demonstrated bactericidal activity more rapid than comparators PHMZ (Rifapentine P, Isoniazid H, Moxifloxacin M, Pyrazinamide Z) and BPaMZ. Modelled cure/relapse data showed that SPa286Sut, SPaSut and SPa656Sut cured 90% of mice in about 1 month, while SPa286, SPaQTBD11 and SPaTBD09 in less than 2 months, faster than PHMZ. Consistent with our previous findings, the fastest-curing regimens centered on a diarylquinoline (S), a nitroimidazole (Pa) and an oxazolidinone (TBD09 or Sut) together with an Rv1625c agonist (TBD11 or 286), DprE1 inhibitor (Q) or a LeuRS inhibitor (656). Notably, significant contributions to sterilizing efficacy were demonstrated for S in all combinations and for Pa, Sut, TBD09, Q and TBD11 or 286 in specific S-containing combinations. These findings suggest potential for these novel agents and combinations to improve treatment of both DS-and DR-TB.

pharmacology and toxicology↗

bioRxiv2026

Nonclinical pharmacokinetics and relative efficacy of the first 25 novel tuberculosis drug combinations from the PAN-TB consortium: Use of the BALB/c relapsing mouse model and combination pharmacokinetics within a modeling-based framework

The Project to Accelerate New Treatments for Tuberculosis (PAN-TB) aims to accelerate development of shorter, simpler and safer pan-TB combinations, effective for use in both Drug Susceptible (DS)- and Drug Resistant (DR)- TB patients. Towards this aim, bactericidal and sterilizing activity of 25 priority 4-drug combinations was evaluated at doses targeting clinically relevant exposures, in the BALB/c relapsing mouse model of TB. The combinations comprised 8 PAN-TB drugs and candidates: bedaquiline (B), pretomanid (Pa), delamanid (Del), quabodepistat (Q), sutezolid (Sut), GSK2556286 (286), GSK3211830 (830) and ganfeborole (GSK3036656, (656)). Combination PK studies in infected mice enabled dose selection and a population-PK approach guided dosing so that compounds should achieve mean AUC0-24 within 2-fold of their clinical target exposures during the efficacy studies. All test combinations showed time-dependent bactericidal activity, with six regimens reducing lung bacterial burdens below the limit of detection with 8 weeks treatment, similar to the comparator BPaMZ (M is moxifloxacin and Z as pyrazinamide). Cure/Relapse data were modelled to derive population time to cure 90% mice (T90) values. Fifteen PAN-TB combinations had T90s of less than 5 months, sterilizing mice faster than the standard of care for drug susceptible TB, RHZE/RH. The best-performing PAN-TB combinations, BPa830Sut, BPa286Sut and BQSut286, cured 90% of mice in less than 3 months. These 3 top-ranked 4-drug combinations are all centered on a diarylquinoline (B)/oxazolidinone (Sut) core, together with the nitroimidazole (Pa) or a DprE1 inhibitor (Q) plus a novel agent such as the LeuRS inhibitor (830) or the Rv1625c agonist (286).

microbiology↗

bioRxiv2024

Genome-wide maps of highly-similar intrachromosomal repeats that mediate ectopic recombination in three human genome assemblies

Repeated sequences spread throughout the genome play important roles in shaping the structure of chromosomes and facilitating the generation of new genomic variation. Through a variety of mechanisms, repeats are involved in generating structural rearrangements such as deletions, duplications, inversions, and translocations, which can have the potential to impact human health. Despite their significance, repetitive regions including tandem repeats, transposable elements, segmental duplications, and low-copy repeats remain a challenge to characterize due to technological limitations inherent to many sequencing methodologies. We performed genome-wide analyses and comparisons of direct and inverted repeated sequences in the latest available human genome reference assemblies including GRCh37 and GRCh38 and the most recent telomere-to-telomere alternate assembly (T2T-CHM13). Overall, the composition and distribution of direct and inverted repeats identified remains similar among the three assemblies but we observed an increase in the number of repeated sequences detected in the T2T-CHM13 assembly versus the reference assemblies. As expected, there is an enrichment of repetitive regions in the short arms of acrocentric chromosomes, which had been previously unresolved in the human genome reference assemblies. We cross-referenced the identified repeats with protein-coding genes across the genome to identify those at risk for being involved in genomic disorders. We observed that certain gene categories, such as olfactory receptors and immune response genes, are enriched among those impacted by repeated sequences likely contributing to human diversity and adaptation. Through this analysis, we have produced a catalogue of direct and inversely oriented repeated sequences across the currently three most widely used human genome assemblies. Bioinformatic analyses of these repeats and their contribution to genome architecture can reveal regions that are most susceptible to genomic instability. Understanding how the architectural genomic features of repeat pairs such as their homology, size and distance can lead to complex genomic rearrangement formation can provide further insights into the molecular mechanisms leading to genomic disorders and genome evolution. Author summaryThis study focused on the characterization of intrachromosomal repeated sequences in the human genome that can play important roles in shaping chromosome structure and generating new genomic variation in three human genome assemblies. We observed an increase in the number of repeated sequence pairs detected in the most recent telomere-to-telomere alternate assembly (T2T-CHM13) compared to the reference assemblies (GRCh37 and GRCh38). We observed an enrichment of repeats in the T2T-CHM13 acrocentric chromosomes, which had been previously unresolved. Importantly, our study provides a catalogue of direct and inverted repeated sequences across three commonly used human genome assemblies, which can aid in the understanding of genomic architecture instability, evolution, and disorders. Our analyses provide insights into repetitive regions in the human genome that may contribute to complex genomic rearrangements

genomics↗