Biology subjects

Lucia, A.

Publications and source records attributed to Lucia, A..

4 recordsLinked to original sources

bioRxiv2025

In vitro pharmacokinetics and pharmacodynamics of the diarylquinoline TBAJ-587 and its metabolites against Mycobacterium tuberculosis

The first-in-class diarylquinoline (DARQ) bedaquiline (BDQ) is in the medicines list for drug-resistant tuberculosis. TBAJ-587 is a next-generation DARQ with improved anti-Mycobacterium tuberculosis (Mtb) activity and reduced cardiac repolarization abnormalities. Methods. The in-vitro efficacy of TBAJ-587 and its main metabolites (M2, M3 and M12) was analyzed under standard (ST) growth conditions, with cholesterol (CHO), or fatty acids (FA) as alternative carbon sources. Minimal inhibitory concentration (MIC) assays and time-kill assays (TKA) linked to drug measurements in bacterial samples were performed to allow correlation of pharmacodynamics (PD) with actual pharmacokinetics (PK). The most active compounds, TBAJ-587 and its M3 metabolite, exhibited broth media and concentration dependent efficacy showing a bactericidal effect at [≥]5x MIC. Bacterial cultures treated with 1x MIC and 2x MIC of TBAJ-587 resumed growth after 28 days and displayed moderate increased MIC values compared to untreated conditions, which were linked to new variants of BDQ resistance mutations in the atpE, atpB, and Rv0678 genes. This study revealed TBAJ-587 and metabolites bind to polystyrene plastic-ware, the most commonly used material in antimicrobial research, being the effective unbound drug concentration dependent on the media composition. PKPD analyses determined that Mtb was killed with lower exposures of TBAJ-587 and M3 than expected in ST and FA broth, suggesting previously underestimated potency in these media. This is the first in-vitro study to precisely link compound activities (PD) to their effective concentration (PK) over time in Mtb cultures, providing improved longitudinal data to feed models for translational research.

pharmacology and toxicology↗

bioRxiv2025

Novel antimicrobial activity of photoactive compounds originally synthesized for industrial applications

The emergence of antimicrobial resistance threatens advances achieved by medicine in the last century. This situation has been aggravated by the suboptimal outcome of screening campaigns to provide novel antibiotics. In this study, we took an alternative approach to discover new chemical scaffolds with antimicrobial activity. We screened a collection of photoactive compounds originally synthesized for industrial purposes and found that 4H-pyran-4-ylidenes are active against Gram-positive bacteria. Compounds belonging to this family displayed dose-dependent bactericidal activity against wild-type Staphylococcus aureus and Methicillin Resistant S. aureus (MRSA). Importantly, they were not cytotoxic to hepatic cell lines at the concentrations at which antimicrobial activity was observed. Resistance to 4H-pyran-4-ylidenes in S. aureus was achieved via mutations in the rny locus, likely via changes in mRNA levels of genes critical for their activity. Overall, we demonstrate that chemical libraries not originally intended for drug discovery can be a fruitful source of chemical diversity for the development of novel antimicrobials.

microbiology↗

bioRxiv2024

alpha-Actinin-3 deficiency protects from the effects of acute cold exposure through altered skeletal muscle Ca2+ and OXPHOS signaling.

Summary / AbstractA nonsense polymorphism in the ACTN3 gene (R577X, rs1815739) results in the loss of the fast skeletal muscle fiber protein -actinin-3 in an estimated 1.5 billion humans worldwide. Homozygosity for this common polymorphism (ACTN3 577XX) does not cause disease but is detrimental to sprint performance in elite athletes. Recently, we reported that ACTN3 577XX humans and Actn3 knockout mice show improved cold tolerance. This was not due to an increase in brown adipose tissue activity or a greater muscle shivering response, but was associated with an increased abundance of slow myosin heavy chain muscle fibers in XX individuals, which in turn increased muscle tone to improve cold tolerance. Using the Actn3 knockout mouse we have now analyzed the molecular and physiological impacts of acute cold exposure (4{degrees}C, for 5 hours) on skeletal muscle. In addition, we used statistical inference of publicly available archaic (Neanderthal and Denisovan) and modern human DNA data to estimate the age of the ACTN3 X-allele and to identify a novel haplotype associated with this variant that provides support for genetic selection in some populations of modern humans. Our results indicate that skeletal muscle of Actn3 knockout mice exhibit higher mitochondrial oxidative phosphorylation abundance and activity than wild-type controls. Following acute cold exposure, we identified reductions in gene ontology pathways associated with metabolism and protein breakdown, which impact muscle mass loss and improved muscle fatigue resistance. Together this provides further evidence for improved cold tolerance in Actn3 knockout mice and ACTN3 577XX individuals. Furthermore, we confirm that the X-allele first appeared in modern humans [~]135,000 years ago, with this variant increasing in frequency in European and Asian populations from as early as 42,000 years ago, which aligns with modern human migration out of Africa. Taken together these data provide additional molecular and functional evidence for a protective advantage of -actinin-3 deficiency following cold exposure, highlighting the importance of skeletal muscle in mammalian thermogenesis and its potential role in the evolution of modern-day humans.

cell biology↗

bioRxiv2019

Physiological predictors of competitive performance in CrossFit(R) athletes

The aim of this study was to determine which physiological variables could predict performance during a CrossFit competition. Fifteen male CrossFit athletes (35 {+/-} 9 years) participated and performed a series of tests (incremental load test for full squat and bench press, jump tests, incremental running test, and Wingate test) that were used as potential predictors of CrossFit performance. Thereafter, they performed the five Workouts of the Day (WODs) corresponding to the CrossFit Games Open 2019, and the relationship between each variable and CrossFit performance was analyzed. Overall Crossfit performance (i.e., final ranking considering all WODs) was significantly related to jump ability, mean and peak power output during the Wingate test, relative maximum strength for the full squat and the bench press, and maximum oxygen uptake and maximum speed during an incremental running test (all p<0.05, r=0.58-0.75), although the relationship of most markers varied depending on the analyzed WOD. Multiple linear regression analysis showed that the combination of maximum oxygen uptake, squat jump ability, and reactive strength index accounted for 81% of the variance in overall CrossFit performance (p=0.0003). CrossFit performance seems dependent on a variety of power-, strength-, and aerobic-related markers, which reflects the complexity of this sport. Improvements in aerobic capacity may help people and athletes in CrossFit performance and well-being. Also, focus on lower body power could be the key to obtain better performance markers.

physiology↗