Biology subjects

Zamora, A.

Publications and source records attributed to Zamora, A..

4 recordsLinked to original sources

bioRxiv2026

SOS-mediated prophage induction constrains resistance evolution to DNA-damaging antibiotics

Most naturally occurring bacteria are lysogens, encoding one or more temperate phages (prophages) integrated into their genome. As prophages are induced by the bacterial SOS response, DNA-damaging antibiotics can trigger SOS-mediated prophage induction, where prophages undergo lytic replication and lyse their host, even at sub-inhibitory concentrations. This prophage-antibiotic synergy therefore sensitizes lysogenic hosts to DNA-damaging antibiotics. However, the mechanism by which prophage-induced sensitization affects the evolution of resistance against these agents is unclear. Here we show that ciprofloxacin-resistant lysogens arise less frequently but exhibit higher levels of resistance following selection. Whole-genome sequencing showed that increased lysogen resistance arose from selection towards mutations in drug targets, efflux pathways, and stress response regulators that reduce antibiotic efficacy or alter SOS induction. Consistent with this result, resistant lysogens exhibited a dampened SOS response, suggesting that prophage induction imposes an additional selective filter on their hosts by eliminating mutants that experience sufficient DNA damage to activate the SOS response. By contrast, prophage carriage had no effect on sensitivity or resistance evolution for antibiotics where DNA damage occurs downstream of the primary mechanism of action. Together, these findings indicate that prophage induction acts as an evolutionary bottleneck that restricts many resistance trajectories while favoring the emergence of rarer, large-effect mutations, potentially accelerating the evolution of high-level resistance.

microbiology↗

bioRxiv2026

The metalloproteinase inhibitor Marimastat improves skeletal muscle regeneration when administered intravenously after myonecrosis induced by the venom of Bothrops asper

Skeletal muscle regeneration is often impaired after acute muscle damage induced by viperid snake venoms, such as that of Bothrops asper, a medically-relevant species in Latin America. It has been shown that traces of venom that remain in the damaged muscle affect myogenic cells in culture, raising the possibility of inhibition of these toxins during the regenerative process as a way to improve regeneration. Using a mouse model of myonecrosis and regeneration, we evaluated the effects of Varespladib (a phospholipase A2 inhibitor) or Marimastat (a metalloproteinase inhibitor) on muscle regeneration when administered intravenously 24 h after the onset of myonecrosis, i.e., after muscle damage has occurred. The regenerative process was evaluated 14 and 28 days after venom injection. Results show that Marimastat, or a combination of both inhibitors, improved the extent of skeletal muscle regeneration and reduced the extent of tissue fibrosis when compared to tissue from mice receiving venom and no inhibitors, as judged by qualitative and quantitative histological assessment. Results underscore the deleterious role of traces of venom components in the damaged muscle during muscle regeneration and suggest that the administration of metalloproteinase inhibitors, or a combination of metalloproteinase and phospholipase A2 inhibitors, even when muscle damage has developed, may be a therapeutic alternative for improving the extent of muscle regeneration.

pharmacology and toxicology↗

bioRxiv2024

Surface remodeling and inversion of cell-matrix interactions underlies community recognition and dispersal in Vibrio cholerae biofilms

Biofilms are ubiquitous surface-associated bacterial communities embedded in an extracellular matrix. While it is commonly assumed that biofilm-dwelling cells are glued together by the matrix, how the cell-matrix interaction depends on the specific biochemistry of the matrix components and how this interaction varies during biofilm growth remains unclear. Here, we investigated cell-matrix interactions in Vibrio cholerae (Vc), the causative agent of cholera. We combine genetics, microscopy, simulation, and biochemical tools to show that Vc cells are not attractive to Vibrio polysaccharide (VPS), the main matrix component, but they can be bridged with each other and to the VPS network through crosslinking by Bap1. Downregulation of VPS and surface trimming by the polysaccharide lyase RbmB cause surface remodeling as biofilms age, shifting the nature of cell-matrix interactions from attractive to repulsive and facilitating cell dispersal as aggregated groups. Our results suggest a new conceptual model in understanding the intricate cell-matrix interaction as the major driver for biofilm development, which is potentially generalizable to certain other biofilm-forming species and exopolysaccharides.

biophysics↗

bioRxiv2023

MICROGLIAL CELL EXPRESSION OF THE TYPE 2 CANNABINOID RECEPTOR REGULATES IMMUNE-MEDIATED NEUROINFLAMMATION

Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype which potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and has implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.

immunology↗