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4. Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics

Author

Dulyayangkul, Punyawee, primary, Beavis, Thomas, additional, Lee, Winnie W. Y., additional, Ardagh, Robbie, additional, Edwards, Frances, additional, Hamilton, Fergus, additional, Head, Ian, additional, Heesom, Kate J., additional, Mounsey, Oliver, additional, Murarik, Marek, additional, Pinweha, Peechanika, additional, Reding, Carlos, additional, Satapoomin, Naphat, additional, Shaw, John M., additional, Takebayashi, Yuiko, additional, Tooke, Catherine L., additional, Spencer, James, additional, Williams, Philip B., additional, and Avison, Matthew B., additional

Published
2024
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5. One Health drivers of antibacterial resistance: Quantifying the relative impacts of human, animal and environmental use and transmission

Author

Avison, Matthew B., Alhusein, Nour, Booton, Ross D., Buller, Henry, Chantong, Boonrat, Charoenlap, Nisanart, Couto, Natacha, Dulyayangkul, Punyawee, Feil, Edward, Gibbon, Marjorie J., Gould, Virginia C., Lambert, Helen, Meeyai, Aronrag, Mongkolsuk, Skorn, Montrivade, Varapon, Pitchforth, Emma, Phoonsawad, Kornrawan, Rangkadilok, Nuchanart, Ratanakorn, Parntep, Reyher, Kristen K., Sakcamduang, Walasinee, Satayavivad, Jutamaad, Singer, Andrew C., Sirikanchana, Kwanrawee, Sringernyuang, Luechai, Suriyo, Tawit, Suwanpakdee, Sarin, Thamlikitkul, Visanu, Turner, Katherine M.E., Vass, Lucy, Wichuwaranan, Kantima, and Wiratsudakul, Anuwat

Published
2021
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6. Genomic epidemiology of third-generation cephalosporin-resistant Escherichia coli from Argentinian pig and dairy farms reveals animal-specific patterns of co-resistance and resistance mechanisms

Author

Mounsey, Oliver, primary, Marchetti, Laura, additional, Parada, Julián, additional, Alarcón, Laura V., additional, Aliverti, Florencia, additional, Avison, Matthew B., additional, Ayala, Carlos S., additional, Ballesteros, Cristina, additional, Best, Caroline M., additional, Bettridge, Judy, additional, Buchamer, Andrea, additional, Buldain, Daniel, additional, Carranza, Alicia, additional, Corti Isgro, Maite, additional, Demeritt, David, additional, Escobar, Maria Paula, additional, Gortari Castillo, Lihuel, additional, Jaureguiberry, María, additional, Lucas, Mariana F., additional, Madoz, L. Vanina, additional, Marconi, María José, additional, Moiso, Nicolás, additional, Nievas, Hernán D., additional, Ramirez Montes De Oca, Marco A., additional, Reding, Carlos, additional, Reyher, Kristen K., additional, Vass, Lucy, additional, Williams, Sara, additional, Giraudo, José, additional, De La Sota, R. Luzbel, additional, Mestorino, Nora, additional, Moredo, Fabiana A., additional, and Pellegrino, Matías, additional

Published
2024
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8. Hound: a novel tool for automated mapping of genotype to phenotype in bacterial genomes assembled de novo.

Author

Reding, Carlos, Satapoomin, Naphat, and Avison, Matthew B

Subjects
BACTERIAL genomes, PHENOTYPES, GENOTYPES, AMINO acid sequence, WHOLE genome sequencing, DRUG resistance in bacteria
Abstract

Increasing evidence suggests that microbial species have a strong within species genetic heterogeneity. This can be problematic for the analysis of prokaryote genomes, which commonly relies on a reference genome to guide the assembly process. Differences between reference and sample genomes will therefore introduce errors in final assembly, jeopardizing the detection from structural variations to point mutations—critical for genomic surveillance of antibiotic resistance. Here we present Hound, a pipeline that integrates publicly available tools to assemble prokaryote genomes de novo , detect user-given genes by similarity to report mutations found in the coding sequence, promoter, as well as relative gene copy number within the assembly. Importantly, Hound can use the query sequence as a guide to merge contigs, and reconstruct genes that were fragmented by the assembler. To showcase Hound, we screened through 5032 bacterial whole-genome sequences isolated from farmed animals and human infections, using the amino acid sequence encoded by blaTEM-1 , to detect and predict resistance to amoxicillin/clavulanate which is driven by over-expression of this gene. We believe this tool can facilitate the analysis of prokaryote species that currently lack a reference genome, and can be scaled either up to build automated systems for genomic surveillance or down to integrate into antibiotic susceptibility point-of-care diagnostics. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Reduced antibacterial drug resistance and blaCTX-M β-lactamase gene carriage in cattle-associated Escherichia coli at low temperatures, at sites dominated by older animals and on pastureland:implications for surveillance

Author

Schubert, Hannah, Morley, Katy, Puddy, Emma F, Arbon, Robert, Findlay, Jacqueline, Mounsey, Oliver, Gould, Virginia C, Vass, Lucy, Evans, Madeleine, Rees, Gwen M, Barrett, David C, Turner, Katy M, Cogan, Tristan A, Avison, Matthew B, and Reyher, Kristen K

Subjects
antibiotic resistance, food-borne pathogens, mathematical modeling, surveillance studies
Abstract

Little is known about the drivers of critically important antibacterial resistance in species with zoonotic potential present on farms (e.g. CTX-M β-lactamase-positive Escherichia coli). We collected samples - monthly, between January 2017 and December 2018 - on 53 dairy farms in South West England along with data for 610 variables concerning antibacterial usage, management practices and meteorological factors. We detected E. coli resistant to amoxicillin, ciprofloxacin, streptomycin and tetracycline, respectively, in 2754/4145 (66%), 263/4145 (6%), 1475/4145 (36%) and 2874/4145 (69%) of all samples from faecally contaminated on-farm and near-farm sites. E. coli positive for blaCTX-M were detected in 224/4145 (5.4%) of samples. Multilevel, multivariable logistic regression showed antibacterial dry cow therapeutic choice (including use of cefquinome or framycetin) to be associated with higher odds of blaCTX-M positivity. Low average monthly ambient temperature was associated with lower odds of blaCTX-ME. coli positivity in samples and with lower odds of finding E. coli resistant to each of the four test antibacterials. This was additional to the effect of temperature on total E. coli density. Furthermore, samples collected close to calves had higher odds of having E. coli resistant to each antibacterial as well as positive for blaCTX-M Samples collected on pastureland had lower odds of having E. coli resistant to amoxicillin or tetracycline as well as lower odds of being positive for blaCTX-MImportance Antibacterial resistance poses a significant threat to human and animal health and global food security. Surveillance for resistance on farms is important for many reasons, including to track the impacts of interventions aimed at reducing the prevalence of resistance. In this longitudinal survey of dairy farm antibacterial resistance, we showed that local temperature - as it changes over the course of a year - was associated with the prevalence of antibacterial-resistant E. coli We also showed that prevalence of resistant E. coli was lower on pastureland and higher in environments inhabited by young animals. These findings have profound implications for routine surveillance and for surveys carried out for research. They provide important evidence that sampling at a single time-point and/or single location on a farm is unlikely to be adequate to accurately determine the status of the farm regarding the presence of samples containing resistant E. coli.

Published
2021
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15. Induction of [beta]-lactamase production in Aeromonas hydrophila is responsive to [beta]-lactam-mediated changes in peptidoglycan composition

Author

Tayler, Amy E., Ayala, Juan A., Niumsup, Pannika, Westphal, Katrin, Baker, Jenny A., Zhang, Lufei, Walsh, Timothy R., Wiedemann, Bernd, Bennett, Peter M., and Avison, Matthew B.

Subjects
Beta lactam antibiotics -- Physiological aspects, Beta lactam antibiotics -- Genetic aspects, Beta lactamases -- Physiological aspects, Beta lactamases -- Genetic aspects, Beta lactamases -- Research, Peptidoglycans -- Physiological aspects, Peptidoglycans -- Genetic aspects, Peptidoglycans -- Research, Aeromonas -- Physiological aspects, Aeromonas -- Genetic aspects, Aeromonas -- Research, Biological sciences
Abstract

We have studied the mechanism by which [beta]-Iactam challenge leads to [beta]-lactamase induction in Aeromonas hydrophila through transposon-insertion mutagenesis. Disruption of the DD-carboxypeptidases/endopeptidases, penicillin-binding protein 4 or BIrY leads to elevated monomer-disaccharide-pentapeptide levels in A. hydrophila peptidoglycan and concomitant overproduction of [beta]-Iactamase through activation of the BIrAB two-component regulatory system. During [beta]-lactam challenge, monomer-disaccharide-pentapeptide levels increase proportionately with [beta]-lactamase production and [beta]-lactamase induction is inhibited by vancomycin, which binds muro-pentapeptides. Taken together, these data strongly suggest that the Aeromonas spp. [beta]-lactamase regulatory sensor kinase, BIrB, responds to the concentration of monomerdisaccharide-pentapeptide in peptidoglycan. DOI 10.1099/mic.0.035220-0

Published
2010

16. YieJ (CbrC) mediates CreBC-dependent colicin E2 tolerance in Escherichia coli

Author

Cariss, S. James L., Constantinidou, Chrystala, Patel, Mala D., Takebayashi, Yuiko, Hobman, Jon L., Penn, Charles W., and Avison, Matthew B.

Subjects
Escherichia coli -- Physiological aspects, Membrane proteins -- Properties, Bacterial proteins -- Properties, Gene expression -- Physiological aspects, Biological sciences
Abstract

Colicin E2-tolerant (known as Cet2) Escherichia coli K-12 mutants overproduce an inner membrane protein, CreD, which is believed to cause the Cet2 phenotype. Here, we show that overproduction of CreD in a Cet2 strain results from hyperactivation of the CreBC two-component regulator, but CreD overproduction is not responsible for the Cet2 phenotype. Through microarray analysis and gene knockout and overexpression studies, we show that overexpression of another CreBC-regulated gene, yieJ (also known as cbrC), causes the Cet2 phenotype. doi: 10.1128/JB.01352-09

Published
2010

17. Trade-Offs between Antibacterial Resistance and Fitness Cost in the Production of Metallo-β-Lactamases by Enteric Bacteria Manifest as Sporadic Emergence of Carbapenem Resistance in a Clinical Setting

Author

Cheung, Ching Hei Phoebe, primary, Alorabi, Mohammed, additional, Hamilton, Fergus, additional, Takebayashi, Yuiko, additional, Mounsey, Oliver, additional, Heesom, Kate J., additional, Williams, Philip B., additional, Williams, O. Martin, additional, Albur, Mahableshwar, additional, MacGowan, Alasdair P., additional, and Avison, Matthew B., additional

Published
2021
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18. One Health drivers of antibacterial resistance: Quantifying the relative impacts of human, animal and environmental use and transmission

Author

Booton, Ross D., primary, Meeyai, Aronrag, additional, Alhusein, Nour, additional, Buller, Henry, additional, Feil, Edward, additional, Lambert, Helen, additional, Mongkolsuk, Skorn, additional, Pitchforth, Emma, additional, Reyher, Kristen K., additional, Sakcamduang, Walasinee, additional, Satayavivad, Jutamaad, additional, Singer, Andrew C., additional, Sringernyuang, Luechai, additional, Thamlikitkul, Visanu, additional, Vass, Lucy, additional, Avison, Matthew B., additional, Turner, Katherine M.E., additional, Booton, Ross D., additional, Chantong, Boonrat, additional, Charoenlap, Nisanart, additional, Couto, Natacha, additional, Dulyayangkul, Punyawee, additional, Gibbon, Marjorie J., additional, Gould, Virginia C., additional, Montrivade, Varapon, additional, Phoonsawad, Kornrawan, additional, Rangkadilok, Nuchanart, additional, Ratanakorn, Parntep, additional, Sirikanchana, Kwanrawee, additional, Suriyo, Tawit, additional, Suwanpakdee, Sarin, additional, Wichuwaranan, Kantima, additional, and Wiratsudakul, Anuwat, additional

Published
2021
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19. Defining the growth conditions and promoter-proximal DNA sequences required for activation of gene expression by creBC in Escherichia coli

Author

Cariss, S. James L., Tayler, Amy E., and Avison, Matthew B.

Subjects
Genetic regulation -- Research, Escherichia coli -- Growth, Escherichia coli -- Genetic aspects, Company growth, Biological sciences
Abstract

CreBC is a two-component system that controls the expression of a number of genes in Escherichia coli (called the cre regulon) that encode diverse functions, including intermediary metabolic enzymes. Using a reporter construct, we have shown that cre regulon gene expression is activated during growth in minimal media when glycolytic carbon sources are being fermented. It also is activated during aerobic growth when fermentation products are being used as carbon sources. CreB and CreC are essential for the activation of cre regulon gene expression, but CreA and CreD, encoded as part of the creABCD gene cluster, are not. CreB binds to a TTCACnnnnnnTTCAC direct repeat (the cre tag) in vitro, and this sequence, which is associated with cre regulon gene promoters, is required for the control of gene expression in vivo. These observations support the hypothesis that CreBC is a functional two-component system involved in the metabolic control of transcription in E. coli and confirm that CreB is a DNA binding transcriptional regulator.

Published
2008

20. Resistance to Ceftazidime/Avibactam Plus Meropenem/Vaborbactam When Both are Used Together Achieved in Four Steps from Metallo-β-Lactamase Negative Klebsiella pneumoniae

Author

Dulyayangkul, Punyawee, Douglas, Edward J. A., Lsstovka, Filip, and Avison, Matthew B

Subjects
polycyclic compounds, biochemical phenomena, metabolism, and nutrition
Abstract

Serine β-lactamases are dominant causes of β-lactam resistance in Klebsiella pneumoniae. Recently, this has driven clinical deployment of the β-lactam/β-lactamase inhibitor pairs ceftazidime/avibactam and meropenem/vaborbactam. We show that four steps: ompK36 and ramR mutation plus carriage of OXA-232 and KPC-3-D178Y variant β-lactamases confer ceftazidime/avibactam and meropenem/vaborbactam resistance when both pairs are used together. These findings have implications for decision making about sequential and combinatorial use of these β-lactam/β-lactamase inhibitor pairs to treat K. pneumoniae infections.

Published
2020
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21. One Health drivers of antibacterial resistance: quantifying the relative impacts of human, animal and environmental use and transmission

Author

Booton, Ross D., Meeyai, Aronrag, Alhusein, Nour, Buller, Henry, Feil, Edward, Lambert, Helen, Mongkolsuk, Skorn, Pitchforth, Emma, Reyher, Kristen K., Sakcamduang, Walasinee, Satayavivad, Jutamaad, Singer, Andrew C., Sringernyuang, Luechai, Thamlikitkul, Visanu, Vass, Lucy, Avison, Matthew B., Turner, Katherine M.E., Booton, Ross D., Meeyai, Aronrag, Alhusein, Nour, Buller, Henry, Feil, Edward, Lambert, Helen, Mongkolsuk, Skorn, Pitchforth, Emma, Reyher, Kristen K., Sakcamduang, Walasinee, Satayavivad, Jutamaad, Singer, Andrew C., Sringernyuang, Luechai, Thamlikitkul, Visanu, Vass, Lucy, Avison, Matthew B., and Turner, Katherine M.E.

Abstract

Objectives: Antibacterial resistance (ABR) is a major global health security threat, with a disproportionate burden on lower-and middle-income countries (LMICs). It is not understood how ‘One Health’, where human health is co-dependent on animal health and the environment, might impact the burden of ABR in LMICs. Thailand’s 2017 “National Strategic Plan on Antimicrobial Resistance” (NSP-AMR) aims to reduce AMR morbidity by 50% through 20% reductions in human and 30% in animal antibacterial use (ABU). There is a need to understand the implications of such a plan within a One Health perspective. Methods: A model of ABU, gut colonisation with extended-spectrum beta-lactamase (ESBL)-producing bacteria and transmission was calibrated using estimates of the prevalence of ESBL-producing bacteria in Thailand. This model was used to project the reduction in human ABR over 20 years (2020–2040) for each One Health driver, including individual transmission rates between humans, animals and the environment, and to estimate the longterm impact of the NSP-AMR intervention. Results: The model predicts that human ABU was the most important factor in reducing the colonisation of humans with resistant bacteria (maximum 65.7–99.7% reduction). The NSP-AMR is projected to reduce human colonisation by 6.0–18.8%, with more ambitious targets (30% reductions in human ABU) increasing this to 8.5–24.9%. Conclusions: Our model provides a simple framework to explain the mechanisms underpinning ABR, suggesting that future interventions targeting the simultaneous reduction of transmission and ABU would help to control ABR more effectively in Thailand.

Published
2021

22. Comparative genomic hybridization detects secondary chromosomal deletions in Escherichia coli K-12 MG1655 mutants and highlights instability in the flhDC region

Author

Hobman, Jon L., Patel, Mala D., Hidalgo-Arroyo, G. Aida, Cariss, S. James L., Avison, Matthew B., Penn, Charles W., and Constantinidou, Chrystala

Subjects
Escherichia coli -- Genetic aspects, Bacterial genetics -- Research, Chromosome deletion -- Research, Biological sciences
Abstract

The use of whole-genome microarrays for monitoring mutagenized or otherwise engineered genetic derivatives is a potentially powerful tool for checking genomic integrity. Using comparative genomic hybridization of a number of unrelated, directed deletion mutants in Escherichia coli K-12 MG1655, we identified unintended secondary genomic deletions in the flhDC region in [DELTA]fnr, [DELTA]crp, and [DELTA]creB mutants. These deletions were confirmed by PCR and phenotypic tests. Our findings show that nonmotile progeny are found in some MG1655 directed deletion mutants, and studies on the effects of gene knockouts should be viewed with caution when the mutants have not been screened for the presence of secondary deletions or confirmed by other methods.

Published
2007

23. Diffusible signal factor-dependent cell-cell signaling and virulence in the nosocomial pathogen Stenotrophomonas maltophilia

Author

Fouhy, Yvonne, Scanlon, Karl, Schouest, Katherine, Spillane, Charles, Crossman, Lisa, Avison, Matthew B., Ryan, Robert P., and Dow, J. Maxwell

Subjects
Virulence (Microbiology) -- Research, Gram-negative bacteria -- Genetic aspects, Gram-negative bacteria -- Research, Drug resistance in microorganisms -- Research, Biological sciences
Abstract

The genome of Stenotrophomonas maltophilia encodes a cell-cell signaling system that is highly related to the diffusible signal factor (DSF)-dependent system of the phytopathogen Xanthomonas campestris. Here we show that in S. maltophilia, DSF signaling controls factors contributing to the virulence and antibiotic resistance of this important nosocomial pathogen.

Published
2007

24. nalD encodes a second repressor of the mexAB-oprM multidrug efflux operon of Pseudomonas aeruginosa

Author

Morita, Yuji, Cao, Lily, Gould, Virginia C., Avison, Matthew B., and Poole, Keith

Subjects
Pseudomonas aeruginosa -- Genetic aspects, Pseudomonas aeruginosa -- Physiological aspects, Gene expression -- Research, Gene mutations -- Research, Genetic research, Biological sciences
Abstract

The Pseudomonas aeruginosa nalD gene encodes a TetR family repressor with homology to the SmeT and TtgR repressors of the smeDEF and ttgABC multidrug efflux systems of Stenotrophomonas maltophilia and Pseudomonas putida, respectively. A sequence upstream of mexAB-oprM and overlapping a second promoter for this efflux system was very similar to the SmeT and TtgR operator sequences, and NalD binding to this region was, in fact, demonstrated. Moreover, increased expression from this promoter was seen in a nalD mutant, consistent with NalD directly controlling mexAB-oprM expression from a second promoter.

Published
2006

25. A high prevalence of bla OXA-48 in Klebsiella (Raoultella) ornithinolytica and related species in hospital wastewater in South West England

Author

Gibbon, Marjorie J., primary, Couto, Natacha, additional, David, Sophia, additional, Barden, Ruth, additional, Standerwick, Richard, additional, Jagadeesan, Kishore, additional, Birkwood, Hollie, additional, Dulyayangkul, Punyawee, additional, Avison, Matthew B., additional, Kannan, Andrew, additional, Kibbey, Dan, additional, Craft, Tim, additional, Habib, Samia, additional, Thorpe, Harry A., additional, Corander, Jukka, additional, Kasprzyk-Hordern, Barbara, additional, and Feil, Edward J., additional

Published
2021
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26. Reduced Antibacterial Drug Resistance and bla CTX-M β-Lactamase Gene Carriage in Cattle-Associated Escherichia coli at Low Temperatures, at Sites Dominated by Older Animals, and on Pastureland: Implications for Surveillance

Author

Schubert, Hannah, primary, Morley, Katy, additional, Puddy, Emma F., additional, Arbon, Robert, additional, Findlay, Jacqueline, additional, Mounsey, Oliver, additional, Gould, Virginia C., additional, Vass, Lucy, additional, Evans, Madeleine, additional, Rees, Gwen M., additional, Barrett, David C., additional, Turner, Katy M., additional, Cogan, Tristan A., additional, Avison, Matthew B., additional, and Reyher, Kristen K., additional

Published
2021
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28. Molecular Epidemiology of Escherichia coli Producing CTX-M and pAmpC β-Lactamases from Dairy Farms Identifies a Dominant Plasmid Encoding CTX-M-32 but No Evidence for Transmission to Humans in the Same Geographical Region

Author

Findlay, Jacqueline, primary, Mounsey, Oliver, additional, Lee, Winnie W. Y., additional, Newbold, Nerissa, additional, Morley, Katy, additional, Schubert, Hannah, additional, Gould, Virginia C., additional, Cogan, Tristan A., additional, Reyher, Kristen K., additional, and Avison, Matthew B., additional

Published
2020
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29. Post-acute COVID-19 associated with evidence of bystander T-cell activation and a recurring antibiotic-resistant bacterial pneumonia

Author

Gregorova, Michaela, primary, Morse, Daniel, additional, Brignoli, Tarcisio, additional, Steventon, Joseph, additional, Hamilton, Fergus, additional, Albur, Mahableshwar, additional, Arnold, David, additional, Thomas, Matthew, additional, Halliday, Alice, additional, Baum, Holly, additional, Rice, Christopher, additional, Avison, Matthew B, additional, Davidson, Andrew D, additional, Santopaolo, Marianna, additional, Oliver, Elizabeth, additional, Goenka, Anu, additional, Finn, Adam, additional, Wooldridge, Linda, additional, Amulic, Borko, additional, Boyton, Rosemary J, additional, Altmann, Daniel M, additional, Butler, David K, additional, McMurray, Claire, additional, Stockton, Joanna, additional, Nicholls, Sam, additional, Cooper, Charles, additional, Loman, Nicholas, additional, Cox, Michael J, additional, Rivino, Laura, additional, and Massey, Ruth C, additional

Published
2020
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36. Molecular epidemiology of cefotaxime-resistant Escherichia coli from dairy farms in South West England identifies a dominant plasmid encoding CTX-M-32

Author

Findlay, Jacqueline, Schubert, Hannah, Morley, Katy, Mounsey, Oliver, Gould, Virginia C., Puddy, Emma F., Newbold, Nerissa, Reyher, Kristen K., Cogan, Tristen A., and Avison, Matthew B.

Subjects
biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses
Abstract

Objectives The objective of this study was to identify the mechanisms of cefotaxime resistance (CTX-R) in 1226 Escherichia coli from 4581 environmental samples collected on 53 dairy farms over a 2-year period in South West England and to characterise a bla CTX-M-32 -producing plasmid, pMOO-32, found to be widely distributed. Methods CTX-R isolates were identified using MIC breakpoint agar plates. β-lactamase genes of interest (GOIs) were detected by PCR. WGS was performed and analysed using the Center for Genomic Epidemiology platform. A plasmid-specific multiplex PCR was designed to indicate the presence of plasmid pMOO-32. Results Amongst 1226 CTX-R isolates, PCR identified bla CTX-M group 1 (549 isolates), bla CTX-M group 9 (100 isolates), bla CMY (12 isolates), bla DHA (1 isolate) and no GOI (566 isolates). WGS analysis of 184 representative isolates identified bla CTX-M (131 isolates; encoding CTX-M-1, -14, -15, -32 and the novel variant, CTX-M-214), bla CMY-2 (6 isolates), bla DHA-1 (one isolate) and presumed AmpC-hyperproduction in 46 isolates that were PCR negative for GOIs. A highly conserved plasmid was identified in 73 isolates, representing 27 E. coli STs. This ∼220 kb IncHI2 plasmid carrying bla CTX-M-32 was designated pMOO-32, was found to be stable in cattle and human transconjugant E. coli even in the absence of selective pressure, and was found by multiplex PCR to be present on 26/53 study farms. Conclusions β-lactamases capable of conferring resistance to third generation cephalosporins were evident on 47/53 farms within this study. This was largely because of the widespread dissemination of an IncHI2 plasmid carrying bla CTX-M-32 .

Published
2019
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37. Evidence for reduced CTX-M carriage in cattle-associated Escherichia coli at low temperatures and on publicly accessible farmland: implications for surveillance and potential for farm-to-human transmission

Author

Schubert, Hannah, Findlay, Jacqueline, Morley, Katy, Puddy, Emma F., Arbon, Robert, Gould, Virginia C., Mounsey, Oliver, Evans, Madeleine, Rees, Gwen M., Barrett, David C., Turner, Katy M., Cogan, Tristan A., Avison, Matthew B., and Reyher, Kristen K.

Subjects
biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses
Abstract

Little is known about the drivers of critically important antibacterial resistance in species with zoonotic potential present on farms (e.g. CTX-M β-lactamase-positive Escherichia coli ). There is also debate about the influence of farms on the circulation of resistance in local human populations. This was a two-year surveillance study on 53 dairy farms. E. coli positive for bla CTX-M were detected in 224/4145 (5.4%) of all samples from faecally-contaminated sites. E. coli positive for bla CTX-M were more prevalent (98/631; 15.5%) in calf samples and less prevalent (12/630; 1.9%) in samples collected from pastureland, including publicly accessible sites. Multilevel, multivariable logistic regression showed antibiotic dry cow therapeutic choice to be associated with risk of bla CTX-M positivity, including use of cefquinome or framycetin; 74% of bla CTX-M -positive E. coli were framycetin-resistant. Low temperature was associated with low risk of bla CTX-M positivity. This was additional to the effect of temperature on total E. coli density, a finding with profound implications for surveillance. There was no evidence that study farms had a significant impact on circulating bla CTX-M plasmids in the local human population: across 296 fully sequenced E. coli isolates, two cattle isolates shared bla CTX-M plasmids with eight urinary isolates collected in parallel.

Published
2019
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38. Resistance to aztreonam, in combination with a bicyclic boronate β-lactamase inhibitor in Escherichia coli identified following mixed culture selection

Author

Cheung, Ching Hei Phoebe, Findlay, Jacqueline, Heesom, Kate J., and Avison, Matthew B.

Subjects
polycyclic compounds, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses
Abstract

Background Bicyclic boronates are a new and potentially important class of β-lactamase inhibitor, with the ability to inhibit β-lactamases from all molecular classes, including mobile metallo-β-lactamases. Objective Our objective was to identify mutants resistant to the actions of the bicyclic boronate inhibitor 2 , when being used in combination with aztreonam. Methods Overnight cultures were plated on to agar containing increasing concentrations of aztreonam with a fixed 10 mg/L concentration of the inhibitor. Resistant derivatives and parent strains were analysed by whole genome sequencing and LC-MS/MS proteomics to identify mechanism of resistance. Results When using a mixed overnight culture containing one Escherichia coli (TEM-1, CTX-M-15, CMY-4 producer) and one Klebsiella pneumoniae (SHV-12, CTX-M-15, NDM-1 producer) mobilisation of an IncX3 plasmid carrying bla SHV-12 from the K. pneumoniae into the E. coli generated an aztreonam/boronate resistant derivative. Conclusions High-level production of three bicyclic boronate susceptible enzymes (CMY-4, CTX-M-15, SHV-12) capable of hydrolysing aztreonam plus TEM-1, which binds the inhibitor, overcomes the fixed inhibitor dose used. This was only identified when using a mixed culture for selection. It would seem prudent that to allow for coalescence of the myriad β-lactamase genes commonly found in bacterial populations colonising humans, this mixed culture approach should be the norm when testing the potential for generating β-lactamase inhibitor resistance in pre-clinical analysis.

Published
2019
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39. Mutation of kvrA causes OmpK35/36 porin downregulation and reduced meropenem/vaborbactam susceptibility in KPC-producing Klebsiella pneumoniae

Author

Dulyayangkul, Punyawee, Wan Ahmad Kamil, Wan Nur Ismah, Douglas, Edward J. A., Avison, Matthew B., Dulyayangkul, Punyawee, Wan Ahmad Kamil, Wan Nur Ismah, Douglas, Edward J. A., and Avison, Matthew B.

Abstract

Meropenem-vaborbactam resistance in Klebsiella pneumoniae isolates is associated with loss-of-function mutations in the OmpK35 and OmpK36 porins. We identify two previously unknown loss-of-function mutations that confer cefuroxime resistance in K. pneumoniae isolates. The proteins lost were NlpD and KvrA; the latter is a transcriptional repressor that controls capsule production. We demonstrate that KvrA loss reduces OmpK35 and OmpK36 porin production, which confers reduced susceptibility to meropenem-vaborbactam in a KPC-3-producing K. pneumoniae isolate.

Published
2020

45. TonB‐dependent uptake of β‐lactam antibiotics in the opportunistic human pathogen Stenotrophomonas maltophilia.

Author

Calvopiña, Karina, Dulyayangkul, Punyawee, Heesom, Kate J., and Avison, Matthew B.

Subjects
STENOTROPHOMONAS maltophilia, BETA lactam antibiotics, ANTIBIOTICS, CEFTAZIDIME, GRAM-negative bacteria, DRUG resistance in bacteria, ANTI-infective agents
Abstract

The β‐lactam antibiotic ceftazidime is one of the handful of drugs with proven clinical efficacy against the important opportunistic human pathogen Stenotrophomonas maltophilia. Here, we show that mutations in the energy transducer TonB, encoded by smlt0009 in S. maltophilia, confer ceftazidime resistance and smlt0009 mutants have reduced uptake of ceftazidime. This breaks the dogma that β‐lactams enter Gram‐negative bacteria only by passive diffusion through outer membrane porins. We also show that ceftazidime‐resistant TonB mutants are cross‐resistant to fluoroquinolone antimicrobials and a siderophore‐conjugated lactivicin antibiotic designed to target TonB‐dependent uptake. This implies that attempts to improve the penetration of antimicrobials into S. maltophilia by conjugating them with TonB substrates will suffer from the fact that β‐lactams and fluoroquinolones coselect resistance to these novel and otherwise promising antimicrobials. Finally, we show that smlt0009 mutants already exist among S. maltophilia clinical isolates and have reduced susceptibility to siderophore‐conjugated lactivicin, despite the in vitro growth impairment seen in smlt0009 mutants selected in the laboratory. [ABSTRACT FROM AUTHOR]

Published
2020
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48. Prediction of Fluoroquinolone Susceptibility Directly from Whole-Genome Sequence Data by Using Liquid Chromatography-Tandem Mass Spectrometry To Identify Mutant Genotypes

Author

Wan Nur Ismah, Wan Ahmad Kamil, primary, Takebayashi, Yuiko, additional, Findlay, Jacqueline, additional, Heesom, Kate J., additional, Jiménez-Castellanos, Juan-Carlos, additional, Zhang, Jay, additional, Graham, Lee, additional, Bowker, Karen, additional, Williams, O. Martin, additional, MacGowan, Alasdair P., additional, and Avison, Matthew B., additional

Published
2018
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49. Structural/mechanistic insights into the efficacy of nonclassical β-lactamase inhibitors against extensively drug resistantStenotrophomonas maltophiliaclinical isolates

Author

Calvopiña, Karina, primary, Hinchliffe, Philip, additional, Brem, Jürgen, additional, Heesom, Kate J., additional, Johnson, Samar, additional, Cain, Ricky, additional, Lohans, Christopher T., additional, Fishwick, Colin W. G., additional, Schofield, Christopher J., additional, Spencer, James, additional, and Avison, Matthew B., additional

Published
2017
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