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    Correlated transcriptional responses provide insights into the synergy mechanisms of the furazolidone, vancomycin and sodium deoxycholate triple combination in Escherichia coli
    (American Society for Microbiology, 2021-10-27) Olivera C; Cox MP; Rowlands GJ; Rakonjac J; Bradford PA
    Effective therapeutic options are urgently needed to tackle antibiotic resistance. Furazolidone (FZ), vancomycin (VAN), and sodium deoxycholate (DOC) show promise as their combination can synergistically inhibit the growth of, and kill, multidrug-resistant Gram-negative bacteria that are classified as critical priority by the World Health Organization. Here, we investigated the mechanisms of action and synergy of this drug combination using a transcriptomics approach in the model bacterium Escherichia coli. We show that FZ and DOC elicit highly similar gene perturbations indicative of iron starvation, decreased respiration and metabolism, and translational stress. In contrast, VAN induced envelope stress responses, in agreement with its known role in peptidoglycan synthesis inhibition. FZ induces the SOS response consistent with its DNA-damaging effects, but we demonstrate that using FZ in combination with the other two compounds enables lower dosages and largely mitigates its mutagenic effects. Based on the gene expression changes identified, we propose a synergy mechanism where the combined effects of FZ, VAN, and DOC amplify damage to Gram-negative bacteria while simultaneously suppressing antibiotic resistance mechanisms. IMPORTANCE Synergistic antibiotic combinations are a promising alternative strategy for developing effective therapies for multidrug-resistant bacterial infections. The synergistic combination of the existing antibiotics nitrofurans and vancomycin with sodium deoxycholate shows promise in inhibiting and killing multidrug-resistant Gram-negative bacteria. We examined the mechanism of action and synergy of these three antibacterials and proposed a mechanistic basis for their synergy. Our results highlight much-needed mechanistic information necessary to advance this combination as a potential therapy.
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    Is the family pet a risk for multidrug resistant infections? : thesis presented in fulfilment of the requirements for the degree of Doctor of Philosophy in Veterinary Science at Massey University, Palmerston North, New Zealand
    (Massey University, 2019) Toombs-Ruane, Leah
    Risk factors for community-acquired urinary tract infections (UTI) caused by extended-spectrum beta-lactamase-(ESBL) and AmpC beta-lactamase-(ACBL) producing Enterobacteriaceae were investigated in a prospective case-control study conducted between August 2015 and September 2017. Both cases and controls were from the Auckland and Northland regions of New Zealand. A telephone questionnaire was delivered to participants, and the results analysed for putative risk factors for human infections. Analysis was performed using regression models, including factors around pet ownership and any other animal contact. Faecal samples were submitted from some households; this included samples from both people and companion animals. Isolates collected from index case urine samples and ESBL- or ACBL-producing faecal samples were sequenced and subsequently analysed through a bioinformatics pipeline. Pet ownership was not found to be a risk for human ESBL- or AmpC-producing infections in this study. Another important finding of this research was that E. coli ST-131 was the most commonly found bacteria associated with the UTI from people recruited into the case-control study. The strains of this sequence type were likely to have entered New Zealand in multiple introductions over the last 20 years. Transmission of ESBL-/ACBLproducing E. coli was also suspected to have occurred within households where a person had been recently infected with the same bacteria (in the form of a UTI) caused by an ESBL-/ACBL-producing Enterobacteriaceae. The results of this study as a whole indicate that while pets may not be a major risk for acquisition of ESBL/ACBL-producing bacteria, they are likely to play a role in the transmission of bacteria within homes and the community, and therefore warrant attention in future work.
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    Pectin degradation and metabolism in Monoglobus pectinilyticus 14T from human faeces : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Microbiology at Massey University, Manawatu, New Zealand
    (Massey University, 2017) Kim, Caroline Chae-hyun
    Pectin is a conspicuous plant polysaccharide, comprising one third of the dry weight of dietary fibre in common vegetables and fruit. Although pectin is almost completely digested by the human gut microbiota, few bacterial species are known to possess a comprehensive glycobiome to challenge the structurally complex pectin. The current understanding of the colonic degradation of pectin is incomplete, as the knowledge has almost exclusively derived from studying the sequestration system of Bacteroides spp. Here I report the isolation and characterization of Monoglobus pectinilyticus, and the sequencing of its genome which so far encodes the most pectin-specialized repertoire of carbohydrate active enzymes (CAZymes) found from the human gut. M. pectinilyticus also possesses an extracellular pectin degradation system consisting of novel protein constituents which did not find significant sequence homology and functional matches using the most up-to-date nucleotide and protein sequence databases. Proteome analysis of M. pectinilyticus using iTRAQ quantification revealed that pectin-degrading CAZymes and the potential constituents of the novel pectin degradation system were differentially up-regulated in response to the availability of pectin. Finally, using quantitative PCR, a positive correlation was observed between the prevalence of M. pectinilyticus and the consumption of fibre, vegetables, and pectin in individuals living in NZ. The discovery of M. pectinilyticus may add a new layer of complexity onto our interpretation of the colonic pectin degradation by presenting a system highly relevant to the pectin-rich diet of humans, and by suggesting a possibility outside the established paradigms of microbial polysaccharide degradation. The presence of M. pectinilyticus and the related uncultured bacteria in the gastrointestinal systems of humans and animals indicated that the organisms of this lineage are frequent terrestrial gut commensals, prompting an investigation into the genomic and molecular properties underlying their carbohydrate degradation potentials.
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    Correlated Transcriptional Responses Provide Insights into the Synergy Mechanisms of the Furazolidone, Vancomycin, and Sodium Deoxycholate Triple Combination in Escherichia coli.
    (27/10/2021) Olivera C; Cox MP; Rowlands GJ; Rakonjac J
    Effective therapeutic options are urgently needed to tackle antibiotic resistance. Furazolidone (FZ), vancomycin (VAN), and sodium deoxycholate (DOC) show promise as their combination can synergistically inhibit the growth of, and kill, multidrug-resistant Gram-negative bacteria that are classified as critical priority by the World Health Organization. Here, we investigated the mechanisms of action and synergy of this drug combination using a transcriptomics approach in the model bacterium Escherichia coli. We show that FZ and DOC elicit highly similar gene perturbations indicative of iron starvation, decreased respiration and metabolism, and translational stress. In contrast, VAN induced envelope stress responses, in agreement with its known role in peptidoglycan synthesis inhibition. FZ induces the SOS response consistent with its DNA-damaging effects, but we demonstrate that using FZ in combination with the other two compounds enables lower dosages and largely mitigates its mutagenic effects. Based on the gene expression changes identified, we propose a synergy mechanism where the combined effects of FZ, VAN, and DOC amplify damage to Gram-negative bacteria while simultaneously suppressing antibiotic resistance mechanisms. IMPORTANCE Synergistic antibiotic combinations are a promising alternative strategy for developing effective therapies for multidrug-resistant bacterial infections. The synergistic combination of the existing antibiotics nitrofurans and vancomycin with sodium deoxycholate shows promise in inhibiting and killing multidrug-resistant Gram-negative bacteria. We examined the mechanism of action and synergy of these three antibacterials and proposed a mechanistic basis for their synergy. Our results highlight much-needed mechanistic information necessary to advance this combination as a potential therapy.
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    Carriage of Extended-Spectrum-Beta-Lactamase- and AmpC Beta-Lactamase-Producing Escherichia coli Strains from Humans and Pets in the Same Households.
    (American Society for Microbiology, 24/11/2020) Toombs-Ruane LJ; Benschop J; French NP; Biggs PJ; Midwinter AC; Marshall JC; Chan M; Drinković D; Fayaz A; Baker MG; Douwes J; Roberts MG; Burgess SA
    Extended-spectrum-beta-lactamase (ESBL)- or AmpC beta-lactamase (ACBL)-producing Escherichia coli bacteria are the most common cause of community-acquired multidrug-resistant urinary tract infections (UTIs) in New Zealand. The carriage of antimicrobial-resistant bacteria has been found in both people and pets from the same household; thus, the home environment may be a place where antimicrobial-resistant bacteria are shared between humans and pets. In this study, we sought to determine whether members (pets and people) of the households of human index cases with a UTI caused by an ESBL- or ACBL-producing E. coli strain also carried an ESBL- or ACBL-producing Enterobacteriaceae strain and, if so, whether it was a clonal match to the index case clinical strain. Index cases with a community-acquired UTI were recruited based on antimicrobial susceptibility testing of urine isolates. Fecal samples were collected from 18 non-index case people and 36 pets across 27 households. Eleven of the 27 households screened had non-index case household members (8/18 people and 5/36 animals) positive for ESBL- and/or ACBL-producing E. coli strains. Whole-genome sequence analysis of 125 E. coli isolates (including the clinical urine isolates) from these 11 households showed that within seven households, the same strain of ESBL-/ACBL-producing E. coli was cultured from both the index case and another person (5/11 households) or pet dog (2/11 households). These results suggest that transmission within the household may contribute to the community spread of ESBL- or ACBL-producing E. coliIMPORTANCEEnterobacteriaceae that produce extended-spectrum beta-lactamases (ESBLs) and AmpC beta-lactamases (ACBLs) are important pathogens and can cause community-acquired illnesses, such as urinary tract infections (UTIs). Fecal carriage of these resistant bacteria by companion animals may pose a risk for transmission to humans. Our work evaluated the sharing of ESBL- and ACBL-producing E. coli isolates between humans and companion animals. We found that in some households, dogs carried the same strain of ESBL-producing E. coli as the household member with a UTI. This suggests that transmission events between humans and animals (or vice versa) are likely occurring within the home environment and, therefore, the community as a whole. This is significant from a health perspective, when considering measures to minimize community transmission, and highlights that in order to manage community spread, we need to consider interventions at the household level.