Biology subjects

Mutti, M.

Publications and source records attributed to Mutti, M..

3 recordsLinked to original sources

bioRxiv2026

A chimeric, half-life extended lysin with a unique mode of action

Anti-staphylococcal lytic agents, such as lysostaphin (LSN), a glycyl-glycyl (Gly-Gly) peptidase, have long been considered for the management of chronic and complicated bacterial infections typically resistant to conventional antibiotics, but their use is restricted by poor pharmacokinetic properties. We generated half-life extended lysostaphin constructs by fusing the lysin - either alone or chimerized with an additional enzymatic cysteine, histidine-dependent amidohydrolases/peptidase (CHAP) domain - to the human IgG1 Fc fragment. The Fc-CHAP-LSN constructs retain high potency against Staphylococcus aureus and coagulase negative staphylococcal strains in vitro and are efficacious in S. aureus ex vivo biofilm models and in vivo sepsis models. A detailed investigation of the Fc-CHAP-LSN mode of action revealed that upon binding to the bacterial cell, but not in solution, LSN mediates its own release by cleaving the Gly-Gly CHAP-LSN linker. The bactericidal activity of Fc-CHAP-LSN is driven by the LSN-catalyzed and target cell-dependent release of free LSN. The half-life extended lysin acts as a pro-drug, unveiling a novel mechanism of targeted release and an alternative approach to half-life extension.

bioengineering↗

bioRxiv2023

Phage activity against Staphylococcus aureus is impaired in plasma and synovial fluid.

S. aureus is a pathogen that frequently causes severe morbidity and phage therapy is being discussed as an alternative to antibiotics for the treatment of S. aureus infections. In this in vitro and animal study, we demonstrated that the activity of anti-staphylococcal phages is severely impaired in plasma and synovial fluid. Despite phage replication in these matrices, lysis of the bacteria was slower than phage propagation, and no reduction of the bacterial population was observed. This phage inhibition is due to a 99% reduction of phage adsorption, already at 10% plasma concentration. Coagulation factors bind S. aureus resulting in the formation of aggregates and blood clots that protect the bacterium from the phages. This was confirmed by the finding that purified fibrinogen is sufficient to impair phage activity. In contrast, dissolution of the clots by tissue plasminogen activator (tPA) partially restored phage activity. Consistent with these in vitro findings, phage treatment did not reduce bacterial burdens in a neutropenic mouse S. aureus thigh infection model. In summary, phage treatment of S. aureus infections may be fundamentally challenging, and more investigation is needed prior to proceeding to in-human trials.

microbiology↗

bioRxiv2020

Machine learning (decision tree analysis) identifies ecological selectivity patterns across the end-Permian mass extinction

Decision tree algorithms are rarely utilized in paleontological research, and here we show that machine learning algorithms can be used to identify determinants of extinction as well as predict extinction risk. This application of decision tree algorithms is important because the ecological selectivity of mass extinctions can reveal critical information on organismic traits as key determinants of extinction and hence the causes of extinction. To understand which factors led to the mass extinction of life during an extreme global warming event, we quantified the ecological selectivity of marine extinctions in the well-studied South China region during the end-Permian mass extinction using the categorized gradient boosting algorithm. We find that extinction selectivity varies between different groups of organisms and that a synergy of multiple environmental stressors best explains the overall end-Permian extinction selectivity pattern. Extinction risk was greater for genera that were limited to deep-water habitats, had a stationary mode of life, possessed a siliceous skeleton or, less critically, had calcitic skeletons. These selective losses directly link the extinction to the environmental effects of rapid injections of carbon dioxide into the ocean-atmosphere system, specifically the combined effects of expanded oxygen minimum zones, rapid warming, and ocean acidification.

evolutionary biology↗