Publications by authors named "Dario L Balacco"

4 Publications

  • Page 1 of 1

Repeated exposure of nosocomial pathogens to silver does not select for silver resistance but does impact ciprofloxacin susceptibility.

Acta Biomater 2021 Jul 28. Epub 2021 Jul 28.

School of Chemical Engineering, University of Birmingham, Edgbaston B15 2TT, United Kingdom. Electronic address:

The rise of antimicrobial resistant bacteria coupled with a void in antibiotic development marks Antimicrobial Resistance as one of the biggest current threats to modern medicine. Antimicrobial metals are being developed and used as alternative anti-infectives, however, the existence of known resistance mechanisms and limited data regarding bacterial responses to long-term metal exposure are barriers to widespread implementation. In this study, a panel of reference and clinical strains of major nosocomial pathogens were subjected to serial dosage cycles of silver and ciprofloxacin. Populations exposed to silver initially showed no change in sensitivity, however, increasingly susceptibility was observed after the 25th cycle. A control experiment with ciprofloxacin revealed a selection for resistance over time, with silver treated bacteria showing faster adaptation. Morphological analysis revealed filamentation in Gram negative species suggesting membrane perturbation, while sequencing of isolated strains identified mutations in numerous genes. These included those encoding for efflux systems, chemosensory systems, stress responses, biofilm formation and respiratory chain processes, although no consistent locus was identified that correlated with silver sensitivity. These results suggest that de novo silver resistance is hard to select in a range of nosocomial pathogens, although silver exposure may detrimentally impact sensitivity to antibiotics in the long term. STATEMENT OF SIGNIFICANCE: The adaptability of microbial life continuously calls for the development of novel antibiotic molecules, however, the cost and risk associated with their discovery have led to a drying up in the pipeline, causing antimicrobial resistance (AMR) to be a major threat to healthcare. From all available strategies, antimicrobial metals and, more specifically, silver showcase large bactericidal spectrum and limited toxic effect which coupled with a large range of processes available for their delivery made these materials as a clear candidate to tackle AMR. Previous reports have shown the ability of this metal to enact a synergistic effect with other antimicrobial therapies, nevertheless, the discovery of Ag resistance mechanisms since the early 70s and limited knowledge on the long term influence of silver on AMR poses a threat to their applicability. The present study provides quantitative data on the influence of silver based therapies on AMR development for a panel of reference and clinical strains of major nosocomial pathogens, revealing that prolonged silver exposure may detrimentally impact sensitivity to antibiotics.
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http://dx.doi.org/10.1016/j.actbio.2021.07.056DOI Listing
July 2021

The mA Writer: Rise of a Machine for Growing Tasks.

Biochemistry 2019 02 27;58(5):363-378. Epub 2018 Dec 27.

School of Biosciences, College of Life and Environmental Sciences , University of Birmingham , Edgbaston, Birmingham B15 2TT , United Kingdom.

The central dogma of molecular biology introduced by Crick describes a linear flow of information from DNA to mRNA to protein. Since then it has become evident that RNA undergoes several maturation steps such as capping, splicing, 3'-end processing, and editing. Likewise, nucleotide modifications are common in mRNA and are present in all organisms impacting on the regulation of gene expression. The most abundant modification found in mRNA is N6-methyladenosine (mA). Deposition of mA is a nuclear process and is performed by a megadalton writer complex primarily on mRNAs, but also on microRNAs and lncRNAs. The mA methylosome is composed of the enzymatic core components METTL3 and METTL14, and several auxiliary proteins necessary for its correct positioning and functioning, which are WTAP, VIRMA, FLACC, RBM15, and HAKAI. The mA epimark is decoded by YTH domain-containing reader proteins YTHDC and YTHDF, but METTLs can act as "readers" as well. Eraser proteins, such as FTO and ALKBH5, can remove the methyl group. Here we review recent progress on the role of mA in regulating gene expression in light of Crick's central dogma of molecular biology. In particular, we address the complexity of the writer complex from an evolutionary perspective to obtain insights into the mechanism of ancient mA methylation and its regulation.
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http://dx.doi.org/10.1021/acs.biochem.8b01166DOI Listing
February 2019

PDZD8 is not the 'functional ortholog' of Mmm1, it is a paralog.

F1000Res 2018 16;7:1088. Epub 2018 Jul 16.

Department of Biosciences, University of Exeter, Exeter, EX4 4QD, UK.

Authors of a recent paper demonstrate that, like ERMES (ER-mitochondria encounter structure) in fungal cells, PDZD8 (PDZ domain containing 8) tethers mitochondria to the ER in mammalian cells. However, identifying PDZD8 as a "functional ortholog" of yeast Mmm1 (maintenance of mitochondrial morphology protein 1) is at odds with the phylogenetic data. PDZD8 and Mmm1 are paralogs, not orthologs, which affects the interpretation of the data with respect to the evolution of ER-mitochondria tethering. Our phylogenetic analyses show that PDZD8 co-occurs with ERMES components in lineages closely related to animals solidifying its identity as a paralog of Mmm1. Additionally, we identify two related paralogs, one specific to flagellated fungi, and one present only in unicellular relatives of animals. These results point to a complex evolutionary history of ER-mitochondria tethering involving multiple gene gains and losses in the lineage leading to animals and fungi.
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http://dx.doi.org/10.12688/f1000research.15523.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069729PMC
September 2019

Heterogeneity and complexity within the nuclease module of the Ccr4-Not complex.

Front Genet 2013 Dec 23;4:296. Epub 2013 Dec 23.

School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park Nottingham, UK.

The shortening of the poly(A) tail of cytoplasmic mRNA (deadenylation) is a pivotal step in the regulation of gene expression in eukaryotic cells. Deadenylation impacts on both regulated mRNA decay as well as the rate of mRNA translation. An important enzyme complex involved in poly(A) shortening is the Ccr4-Not deadenylase. In addition to at least six non-catalytic subunits, it contains two distinct subunits with ribonuclease activity: a Caf1 subunit, characterized by a DEDD (Asp-Glu-Asp-Asp) domain, and a Ccr4 component containing an endonuclease-exonuclease-phosphatase (EEP) domain. In vertebrate cells, the complexity of the complex is further increased by the presence of paralogs of the Caf1 subunit (encoded by either CNOT7 or CNOT8) and the occurrence of two Ccr4 paralogs (encoded by CNOT6 or CNOT6L). In plants, there are also multiple Caf1 and Ccr4 paralogs. Thus, the composition of the Ccr4-Not complex is heterogeneous. The potential differences in the intrinsic enzymatic activities of the paralogs will be discussed. In addition, the potential redundancy, cooperation, and/or the extent of unique roles for the deadenylase subunits of the Ccr4-Not complex will be reviewed. Finally, novel approaches to study the catalytic roles of the Caf1 and Ccr4 subunits will be discussed.
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http://dx.doi.org/10.3389/fgene.2013.00296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870282PMC
December 2013
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