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2. Phage-induced efflux down-regulation boosts antibiotic efficacy.

Author

Kraus, Samuel, Fletcher, Megan L., Łapińska, Urszula, Chawla, Krina, Baker, Evan, Attrill, Erin L., O'Neill, Paul, Farbos, Audrey, Jeffries, Aaron, Galyov, Edouard E., Korbsrisate, Sunee, Barnes, Kay B., Harding, Sarah V., Tsaneva-Atanasova, Krasimira, Blaskovich, Mark A. T., and Pagliara, Stefano

Subjects
BACTERIOPHAGES, ANTIBIOTICS, BURKHOLDERIA infections, BACTERIAL population, BACTERIAL diseases, BURKHOLDERIA
Abstract

The interactions between a virus and its host vary in space and time and are affected by the presence of molecules that alter the physiology of either the host or the virus. Determining the molecular mechanisms at the basis of these interactions is paramount for predicting the fate of bacterial and phage populations and for designing rational phage-antibiotic therapies. We study the interactions between stationary phase Burkholderia thailandensis and the phage ΦBp-AMP1. Although heterogeneous genetic resistance to phage rapidly emerges in B. thailandensis, the presence of phage enhances the efficacy of three major antibiotic classes, the quinolones, the beta-lactams and the tetracyclines, but antagonizes tetrahydrofolate synthesis inhibitors. We discovered that enhanced antibiotic efficacy is facilitated by reduced antibiotic efflux in the presence of phage. This new phage-antibiotic therapy allows for eradication of stationary phase bacteria, whilst requiring reduced antibiotic concentrations, which is crucial for treating infections in sites where it is difficult to achieve high antibiotic concentrations. Author summary: Bacteriophages are viruses that infect and kill bacteria and therefore are considered to be a very valuable alternative to the antibiotic molecules that are currently employed in the clinic but towards which bacteria are becoming increasingly resistant. Here we show that when infected with a bacteriophage termed ΦBp-AMP1, the bacterium Burkholderia thailandensis becomes more susceptible to three major antibiotic classes routinely employed to treat infections caused by Burkholderia. We discovered that enhanced antibiotic efficacy in the presence of this bacteriophage is due to a decreased capability of the bacterium to expel antibiotics when it is infected with this bacteriophage. Understanding how bacteriophages and antibiotic molecules interact with each other is essential for optimizing bacteriophage-antibiotic therapy against bacterial infections. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Phage-induced efflux down-regulation boosts antibiotic efficacy

Author

Kraus, Samuel, primary, Łapińska, Urszula, additional, Chawla, Krina, additional, Baker, Evan, additional, Attrill, Erin L, additional, O’Neill, Paul, additional, Farbos, Audrey, additional, Jeffries, Aaron, additional, Galyov, Edouard E., additional, Korbsrisate, Sunee, additional, Barnes, Kay B., additional, Harding, Sarah V, additional, Tsaneva-Atanasova, Krasimira, additional, Blaskovich, Mark A T, additional, and Pagliara, Stefano, additional

Published
2023
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5. In Vitro Activity of Novel Topoisomerase Inhibitors against Francisella tularensis and Burkholderia pseudomallei

Author

Whelan, Adam O., primary, Cooper, Ian, additional, Ooi, Nicola, additional, Orr, David, additional, Blades, Kevin, additional, Kirkham, James, additional, Lyons, Amanda, additional, Barnes, Kay B., additional, Richards, Mark I., additional, Salisbury, Anne-Marie, additional, Craighead, Mark, additional, and Harding, Sarah V., additional

Published
2023
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7. Differences in the gut microbiota between Gurkhas and soldiers of British origin.

Author

Troth, Thomas D., McInnes, Ross S., Dunn, Steven J., Mirza, Jeremy, Whittaker, Annalise H., Goodchild, Sarah A., Loman, Nicholas J., Harding, Sarah V., and van Schaik, Willem

Subjects
GUT microbiome, MILITARY personnel, MULTIDIMENSIONAL scaling
Abstract

Previous work indicated that the incidence of travellers' diarrhoea (TD) is higher in soldiers of British origin, when compared to soldiers of Nepalese descent (Gurkhas). We hypothesise that the composition of the gut microbiota may be a contributing factor in the risk of developing TD in soldiers of British origin. This study aimed to characterise the gut microbial composition of Gurkha and non-Gurkha soldiers of the British Army. Recruitment of 38 soldiers (n = 22 Gurkhas, n = 16 non-Gurkhas) and subsequent stool collection, enabled shotgun metagenomic sequencing-based analysis of the gut microbiota. The microbiota of Gurkhas had significantly (P < 0.05) lower diversity, for both Shannon and Simpson diversity indices, using species level markers than the gut microbiota of non-Gurkha soldiers. Non-metric Multidimensional Scaling (NMDS) of the Bray-Curtis distance matrix revealed a significant difference in the composition of the gut microbiota between Gurkhas and non-Gurkha soldiers, at both the species level (P = 0.0178) and the genus level (P = 0.0483). We found three genera and eight species that were significantly enriched in the non-Gurkha group and one genus (Haemophilus) and one species (Haemophilus parainfluenzae) which were enriched in the Gurkha group. The difference in the microbiota composition between Gurkha soldiers and soldiers of British origin may contribute to higher colonization resistance against diarrhoeal pathogens in the former group. Our findings may enable further studies into interventions that modulate the gut microbiota of soldiers to prevent TD during deployment. [ABSTRACT FROM AUTHOR]

Published
2023
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8. The BALB/c Mouse Model for the Evaluation of Therapies to Treat Infections with Aerosolized Burkholderia pseudomallei

Author

Nelson, Michelle, primary, Barnes, Kay B., additional, Davies, Carwyn H., additional, Cote, Christopher K., additional, Meinig, J. Matthew, additional, Biryukov, Sergei S., additional, Dyer, David N., additional, Frick, Ondraya, additional, Heine, Henry, additional, Pfefferle, Denise A., additional, Horstman-Smith, Amanda, additional, Barbaras, Julie, additional, and Harding, Sarah V., additional

Published
2023
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11. An Investigation into the Re-Emergence of Disease Following Cessation of Antibiotic Treatment in Balb/c Mice Infected with Inhalational Burkholderia pseudomallei

Author

Laws, Thomas R., primary, Barnes, Kay B., additional, Jenner, Dominic C., additional, Núñez, Alejandro, additional, Richards, Mark I., additional, Thwaite, Joanne E., additional, Vente, Andreas, additional, Rushton, David, additional, Nelson, Michelle, additional, and Harding, Sarah V., additional

Published
2022
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15. A Burkholderia pseudomallei Toxin Inhibits Helicase Activity of Translation Factor elF4A

Author

Cruz-Migoni, Abimael, Hautbergue, Guillaume M., Artymiuk, Peter J., Baker, Patrick J., Bokori-Brown, Monika, Chang, Chung-Te, Dickman, Mark J., Essex-Lopresti, Angela, Harding, Sarah V., Mahadi, Nor Muhammad, Marshall, Laura E., Mobbs, George W., Mohamed, Rahmah, Nathan, Sheila, Ngugi, Sarah A., Ong, Catherine, Ooi, Wen Fong, Partridge, Lynda J., Phillips, Helen L., Raih, M. Firdaus, Ruzheinikov, Sergei, Sarkar-Tyson, Mitali, Sedelnikova, Svetlana E., Smither, Sophie J., Tan, Patrick, Titball, Richard W., Wilson, Stuart A., and Rice, David W.

Published
2011

22. Influence of pH on the activity of finafloxacin against extracellular and intracellular Burkholderia thailandensis, Yersinia pseudotuberculosis and Francisella philomiragia and on its cellular pharmacokinetics in THP-1 monocytes.

Author

UCL - SSS/LDRI - Louvain Drug Research Institute, Chalhoub, Houssein, Harding, Sarah V, Tulkens, Paul M., Van Bambeke, Françoise, UCL - SSS/LDRI - Louvain Drug Research Institute, Chalhoub, Houssein, Harding, Sarah V, Tulkens, Paul M., and Van Bambeke, Françoise

Abstract

Burkholderia pseudomallei, Yersinia pestis and Francisella tularensis are facultative intracellular bacteria causing life-threatening infections. We have (a) compared the activity of finafloxacin (a fluoroquinolone in development showing improved activity at acidic pH) with that of ciprofloxacin, levofloxacin and imipenem against the extracellular and intracellular (THP-1 monocytes) forms of infection by attenuated surrogates of these species (B. thailandensis, Y. pseudotuberculosis, F. philomiragia) and (b) assessed finafloxacin cellular pharmacokinetics (accumulation, distribution, efflux). Bacteria in broth or in infected monocytes were exposed to antibiotics at pH 7.4 or 5.5 for 24 hr. Maximal relative efficacies (E) and static concentrations (C) were calculated using the Hill equation (concentration-response curves). Finafloxacin pharmacokinetics in cells at pH 7.4 or 5.5 was investigated using C-labelled drug. Extracellularly, all drugs sterilized the cultures, with finafloxacin being two to six times more potent at acidic pH. Intracellularly, E reached the limit of detection (4-5 log cfu decrease) for finafloxacin against all species, but only against B. thailandensis and F. philomiragia for ciprofloxacin and levofloxacin, while imipenem caused less than 2 log cfu decrease for all species. At acid pH, C shifted to two to five times lower values for finafloxacin and to one to four times higher values for the other drugs. Finafloxacin accumulated in THP-1 cells by approximately fivefold at pH 7.4 but up to 20-fold at pH 5.5, and distributed in the cytosol. Fluoroquinolones have proven to be effective in reducing the intracellular reservoirs of B. thailandensis, Y. pseudotuberculosis and F. philomiragia, with finafloxacin demonstrating an additional advantage in acidic environments.

Published
2020

24. Global map of growth-regulated gene expression in Burkholderia pseudomallei, the causative agent of melioidosis

Author

Rodrigues, Fiona, Sarkar-Tyson, Mitali, Harding, Sarah V., Sim, Siew Hoon, Chua, Hui Hoon, Lin, Chi Ho, Han, Xu, Karuturi, R. Krishna M., Sung, Ken, Yu, Kun, Chen, Wei, Atkins, Timothy P., Titball, Richard W., and Tan, Patrick

Subjects
Gene expression -- Research, Pseudomonas -- Genetic aspects, Pseudomonas -- Physiological aspects, Messenger RNA -- Research, Genetic research, Biological sciences
Abstract

Many microbial pathogens express specific virulence traits at distinct growth phases. To understand the molecular pathways linking bacterial growth to pathogenicity, we have characterized the growth transcriptome of Burkholderia pseudomallei, the causative agent of melioidosis. Using a fine-scale sampling approach, we found approximately 17% of all B. pseudomallei genes displaying regulated expression during growth in rich medium, occurring as broad waves of functionally coherent gene expression tightly associated with distinct growth phases and transition points. We observed regulation of virulence genes across all growth phases and identified serC as a potentially new virulence factor by virtue of its coexpression with other early-phase virulence genes, serC-disrupted B. pseudomallei strains were serine auxotrophs and in mouse infection assays exhibited a dramatic attenuation of virulence compared to wild-type B. pseudomallei. Immunization of mice with serC-disrupted B. pseudomallei also conferred protection against subsequent challenges with different wild-type B. pseudomallei strains. At a genomic level, early-phase genes were preferentially localized on chromosome 1, while stationary-phase genes were significantly biased towards chromosome 2. We detected a significant level of chromosomally clustered gene expression, allowing us to predict ~100 potential operons in the B. pseudomallei genome. We computationally and experimentally validated these operons by showing that genes in these regions are preferentially transcribed in the same 5' [right arrow] 3' direction, possess significantly shorter intergenic lengths than the overall genome, and are expressed as a common mRNA transcript. The availability of this transcriptome map provides an important resource for understanding the transcriptional architecture of B. pseudomallei.

Published
2006

33. Establishing an In Vivo Imaging Capability in High-Containment

Author

Flick-Smith, Helen C., primary, Commander, Nicola J., additional, Scott, Andrew E., additional, Thomas, Richard J., additional, Brown, Mark A., additional, Richards, Mark I., additional, Scott, Joanne C., additional, Martin, Kevin R., additional, Harding, Sarah V., additional, and Atkins, Helen S., additional

Published
2016
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37. The Cluster 1 Type VI Secretion System Is a Major Virulence Determinant in Burkholderia pseudomallei

Author

Burtnick, Mary N., primary, Brett, Paul J., additional, Harding, Sarah V., additional, Ngugi, Sarah A., additional, Ribot, Wilson J., additional, Chantratita, Narisara, additional, Scorpio, Angelo, additional, Milne, Timothy S., additional, Dean, Rachel E., additional, Fritz, David L., additional, Peacock, Sharon J., additional, Prior, Joanne L., additional, Atkins, Timothy P., additional, and DeShazer, David, additional

Published
2011
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38. Development of reagents and assays for the detection of pathogenic Burkholderia species

Author

Qazi, Omar, primary, Rani, Mridula, additional, Gnanam, Annie J., additional, Cullen, Thomas W., additional, Stead, Christopher M., additional, Kensing, Haley, additional, McCaul, Kate, additional, Ngugi, Sarah, additional, Prior, Joann L., additional, Lipka, Alexandria, additional, Nagy, Judit M., additional, Whitlock, Gregory C., additional, Judy, Barbara M., additional, Harding, Sarah V., additional, Titball, Richard W., additional, Sidhu, Sachdev S., additional, Trent, M. Stephen, additional, Kitto, G. Barrie, additional, Torres, Alfredo, additional, Estes, D. Mark, additional, Iverson, Brent, additional, Georgiou, George, additional, and Brown, Katherine A., additional

Published
2011
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40. Lipopolysaccharide from Burkholderia thailandensis E264 provides protection in a murine model of melioidosis

Author

Ngugi, Sarah A., primary, Ventura, Valeria V., additional, Qazi, Omar, additional, Harding, Sarah V., additional, Kitto, G. Barrie, additional, Estes, D. Mark, additional, Dell, Anne, additional, Titball, Richard W., additional, Atkins, Timothy P., additional, Brown, Katherine A., additional, Hitchen, Paul G., additional, and Prior, Joann L., additional

Published
2010
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44. A Bioluminescent Francisella tularensisSCHU S4 Strain Enables Noninvasive Tracking of Bacterial Dissemination and the Evaluation of Antibiotics in an Inhalational Mouse Model of Tularemia

Author

Hall, Charlotte A., Flick-Smith, Helen C., Harding, Sarah V., Atkins, Helen S., and Titball, Richard W.

Abstract

ABSTRACTBioluminescence imaging (BLI) enables real-time, noninvasive tracking of infection in vivoand longitudinal infection studies. In this study, a bioluminescent Francisella tularensisstrain, SCHU S4-lux, was used to develop an inhalational infection model in BALB/c mice. Mice were infected intranasally, and the progression of infection was monitored in real time using BLI. A bioluminescent signal was detectable from 3 days postinfection (3 dpi), initially in the spleen and then in the liver and lymph nodes, before finally becoming systemic. The level of bioluminescent signal correlated with bacterial numbers in vivo, enabling noninvasive quantification of bacterial burdens in tissues. Treatment with levofloxacin (commencing at 4 dpi) significantly reduced the BLI signal. Furthermore, BLI was able to distinguish noninvasively between different levofloxacin treatment regimens and to identify sites of relapse following treatment cessation. These data demonstrate that BLI and SCHU S4-luxare suitable for the study of F. tularensispathogenesis and the evaluation of therapeutics for tularemia.

Published
2016
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45. Establishing an In VivoImaging Capability in High-Containment

Author

Flick-Smith, Helen C., Commander, Nicola J., Scott, Andrew E., Thomas, Richard J., Brown, Mark A., Richards, Mark I., Scott, Joanne C., Martin, Kevin R., Harding, Sarah V., and Atkins, Helen S.

Abstract

Whole body imaging technologies, coupled with the generation of stable light emitting strains of infectious agents, make it possible to monitor the location and kinetics of agent growth inside an animal by noninvasive nonterminal methodologies throughout the course of the infection. However, imaging of viable hazardous pathogens, such as Yersinia pestis, requires specialized containment facilities to prevent contamination of both personnel and the wider environment. Here we describe the successful establishment of an in vivobioimaging capability specifically addressing the requirement for safe and secure work with hazard group 3 pathogens and demonstrate its utility for imaging mice infected with a bioluminescence producing strain of Y. pestis.

Published
2016
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46. CD4.

Author

Chu, Karen K., Tippayawat, Patcharaporn, Walker, Nicola J., Harding, Sarah V., Atkins, Helen S., Maillere, Bernard, Bancroft, Gregory J., Lertmemongkolchai, Ganjana, and Altmann, Daniel M.

Abstract

Burkholderia pseudomallei causes melioidosis, a disease with a wide range of possible outcomes, from seroconversion and dormancy to sepsis and death. This spectrum of host-pathogen interactions poses challenging questions about the heterogeneity in immunity to B. pseudomallei. Models show protection to be dependent on CD4 [ABSTRACT FROM AUTHOR]

Published
2011
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47. The nematode Panagrellus redivivus is susceptible to killing by human pathogens at 37°C

Author

Laws, Thomas R., Smith, Simon A., Smith, Martin P., Harding, Sarah V., Atkins, Timothy P., and Titball, Richard W.

Subjects
CAENORHABDITIS elegans, PROKARYOTES, FUNGUS-bacterium relationships, ENTEROBACTERIACEAE
Abstract

Abstract: Caenorhabditis elegans has been used as a host for the study of bacteria that cause disease in mammals. However, a significant limitation of the model is that C. elegans is not viable at 37°C. We report that the gonochoristic nematode Panagrellus redivivus survives at 37°C and maintains its life cycle at temperatures up to and including 31.5°C. The C. elegans pathogens Pseudomonas aeruginosa, Salmonella enterica, Staphylococcus aureus, but not Yersinia pseudotuberculosis, reduced P. redivivus lifespan. Of four strains of Burkholderia multivorans tested, one reduced P. redivivus lifespan at both temperatures, one was avirulent at both temperatures and two strains reduced P. redivivus lifespan only at 37°C. The mechanism by which one of these strains killed P. redivivus at 37°C, but not at 25°C, was investigated further. Killing required viable bacteria, did not involve bacterial invasion of tissues, is unlikely to be due to a diffusible, bacterial toxin and was not associated with increased numbers of live bacteria within the intestine of the worm. We believe B. multivorans may kill P. redivivus by a temperature-regulated mechanism similar to B. pseudomallei killing of C. elegans. [Copyright &y& Elsevier]

Published
2005
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48. Age influences resistance of Caenorhabditis elegans to killing by pathogenic bacteria

Author

Laws, Thomas R., Harding, Sarah V., Smith, Martin P., Atkins, Timothy P., and Titball, Richard W.

Subjects
*CAENORHABDITIS elegans, *PATHOGENIC bacteria, *AGE, *PATHOGENIC microorganisms
Abstract

Caenorhabditis elegans has previously been proposed as an alternative host for models of infectious disease caused by human pathogens. When exposed to some human pathogenic bacteria, the life span of nematodes is significantly reduced. We have shown that mutations in the age-1, and/or age-2 genes of C. elegans, that normally enhance life expectancy, can also increase resistance to killing by the bacterial pathogens Pseudomonas aeruginosa, Salmonella enterica var. Typhimurium, Burkholderia cepacia or Yersinia pseudotuberculosis. We also found that the rate at which wild-type C. elegans was killed by the bacterial pathogens tested increased as nematodes aged. In the case of P. aeruginosa infection, the difference in life span of wild type and age-1 mutants of C. elegans was not due to differences in the level of bacterial colonisation of the gut. [Copyright &y& Elsevier]

Published
2004
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49. Characterization of the Burkholderia pseudomalleiK96243 Capsular Polysaccharide I Coding Region

Author

Cuccui, Jon, Milne, Timothy S., Harmer, Nicholas, George, Alison J., Harding, Sarah V., Dean, Rachel E., Scott, Andrew E., Sarkar-Tyson, Mitali, Wren, Brendan W., Titball, Richard W., and Prior, Joann L.

Abstract

Burkholderia pseudomalleiis the causative agent of melioidosis, a disease endemic to regions of Southeast Asia and Northern Australia. Both humans and a range of other animal species are susceptible to melioidosis, and the production of a group 3 polysaccharide capsule in B. pseudomalleiis essential for virulence. B. pseudomalleicapsular polysaccharide (CPS) I comprises unbranched manno-heptopyranose residues and is encoded by a 34.5-kb locus on chromosome 1. Despite the importance of this locus, the role of all of the genes within this region is unclear. We inactivated 18 of these genes and analyzed their phenotype using Western blotting and immunofluorescence staining. Furthermore, by combining this approach with bioinformatic analysis, we were able to develop a model for CPS I biosynthesis and export. We report that inactivating gmhA, wcbJ, and wcbNin B. pseudomalleiK96243 retains the immunogenic integrity of the polysaccharide despite causing attenuation in the BALB/c murine infection model. Mice immunized with the B. pseudomalleiK96243 mutants lacking a functional copy of either gmhAor wcbJwere afforded significant levels of protection against a wild-type B. pseudomalleiK96243 challenge.

Published
2012
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50. A Burkholderia pseudomalleiMacrophage Infectivity Potentiator-Like Protein Has Rapamycin-Inhibitable Peptidylprolyl Isomerase Activity and Pleiotropic Effects on Virulence

Author

Norville, Isobel H., Harmer, Nicholas J., Harding, Sarah V., Fischer, Gunter, Keith, Karen E., Brown, Katherine A., Sarkar-Tyson, Mitali, and Titball, Richard W.

Abstract

ABSTRACTMacrophage infectivity potentiators (Mips) are a group of virulence factors encoded by pathogenic bacteria such as Legionella, Chlamydia, and Neisseriaspecies. Mips are part of the FK506-binding protein (FKBP) family, whose members typically exhibit peptidylprolyl cis-transisomerase (PPIase) activity which is inhibitable by the immunosuppressants FK506 and rapamycin. Here we describe the identification and characterization of BPSS1823, a Mip-like protein in the intracellular pathogen Burkholderia pseudomallei. Recombinant BPSS1823 protein has rapamycin-inhibitable PPIase activity, indicating that it is a functional FKBP. A mutant strain generated by deletion of BPSS1823in B. pseudomalleiexhibited a reduced ability to survive within cells and significant attenuation in vivo, suggesting that BPSS1823 is important for B. pseudomalleivirulence. In addition, pleiotropic effects were observed with a reduction in virulence mechanisms, including resistance to host killing mechanisms, swarming motility, and protease production.

Published
2011
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