Overview
Qualifications
PhD Biological Sciences (Exeter)
Research
Research projects
2013-15: Filling the target void: Identification of novel antibacterial therapeutics
Work includes:
- Constructing deletion or conditional mutants in genes predicted to be essential in either growth or virulence
- Determine the phenotype of these mutants in appropriate assays
- Collaborate with biochemists to solve the protein structure of novel targets and to design inhibitors as therapeutics.
PhD project:
2009-13: Identification and characterisation of Toxin-antitoxin systems in Burkholderia pseudomallei
The aim of this project was to identify novel Toxin-antitoxin systems in B pseudomallei, the causative agent of melioidosis and elucidate their biological role in persister cell formation and chronic persistent disease.
Grants/Funding:
- Defence Science and Technology Laboratory (DSTL)
Publications
Key publications | Publications by category | Publications by year
Publications by category
Journal articles
Butt A, Higman VA, Williams C, Crump MP, Hemsley CM, Harmer N, Titball RW (2014). The HicA toxin from Burkholderia pseudomallei has a role in persister cell formation.
Biochem J,
459(2), 333-344.
Abstract:
The HicA toxin from Burkholderia pseudomallei has a role in persister cell formation.
TA (toxin-antitoxin) systems are widely distributed amongst bacteria and are associated with the formation of antibiotic tolerant (persister) cells that may have involvement in chronic and recurrent disease. We show that overexpression of the Burkholderia pseudomallei HicA toxin causes growth arrest and increases the number of persister cells tolerant to ciprofloxacin or ceftazidime. Furthermore, our data show that persistence towards ciprofloxacin or ceftazidime can be differentially modulated depending on the level of induction of HicA expression. Deleting the hicAB locus from B. pseudomallei K96243 significantly reduced persister cell frequencies following exposure to ciprofloxacin, but not ceftazidime. The structure of HicA(H24A) was solved by NMR and forms a dsRBD-like (dsRNA-binding domain-like) fold, composed of a triple-stranded β-sheet, with two helices packed against one face. The surface of the protein is highly positively charged indicative of an RNA-binding protein and His24 and Gly22 were functionality important residues. This is the first study demonstrating a role for the HicAB system in bacterial persistence and the first structure of a HicA protein that has been experimentally characterized.
Abstract.
Author URL.
Full text.
Butt A, Müller C, Harmer N, Titball RW (2013). Identification of type II toxin-antitoxin modules in Burkholderia pseudomallei.
FEMS Microbiol Lett,
338(1), 86-94.
Abstract:
Identification of type II toxin-antitoxin modules in Burkholderia pseudomallei.
Type II toxin-antitoxin (TA) systems are believed to be widely distributed amongst bacteria although their biological functions are not clear. We have identified eight candidate TA systems in the genome of the human pathogen Burkholderia pseudomallei. Five of these were located in genome islands. of the candidate toxins, BPSL0175 (RelE1) or BPSS1060 (RelE2) caused growth to cease when expressed in Escherichia coli, whereas expression of BPSS0390 (HicA) or BPSS1584 (HipA) (in an E. coli ΔhipBA background) caused a reduction in the number of culturable bacteria. The cognate antitoxins could restore growth and culturability of cells.
Abstract.
Author URL.
Full text.
Butt A, Muller C, Harmer N, Titball RW (2013). Identification of type II toxin-antitoxin modules in Burkholderia pseudomallei. FEMS Microbiology Letters, 338(1), 86-94.
Publications by year
2014
Butt A, Higman VA, Williams C, Crump MP, Hemsley CM, Harmer N, Titball RW (2014). The HicA toxin from Burkholderia pseudomallei has a role in persister cell formation.
Biochem J,
459(2), 333-344.
Abstract:
The HicA toxin from Burkholderia pseudomallei has a role in persister cell formation.
TA (toxin-antitoxin) systems are widely distributed amongst bacteria and are associated with the formation of antibiotic tolerant (persister) cells that may have involvement in chronic and recurrent disease. We show that overexpression of the Burkholderia pseudomallei HicA toxin causes growth arrest and increases the number of persister cells tolerant to ciprofloxacin or ceftazidime. Furthermore, our data show that persistence towards ciprofloxacin or ceftazidime can be differentially modulated depending on the level of induction of HicA expression. Deleting the hicAB locus from B. pseudomallei K96243 significantly reduced persister cell frequencies following exposure to ciprofloxacin, but not ceftazidime. The structure of HicA(H24A) was solved by NMR and forms a dsRBD-like (dsRNA-binding domain-like) fold, composed of a triple-stranded β-sheet, with two helices packed against one face. The surface of the protein is highly positively charged indicative of an RNA-binding protein and His24 and Gly22 were functionality important residues. This is the first study demonstrating a role for the HicAB system in bacterial persistence and the first structure of a HicA protein that has been experimentally characterized.
Abstract.
Author URL.
Full text.
2013
Butt A, Müller C, Harmer N, Titball RW (2013). Identification of type II toxin-antitoxin modules in Burkholderia pseudomallei.
FEMS Microbiol Lett,
338(1), 86-94.
Abstract:
Identification of type II toxin-antitoxin modules in Burkholderia pseudomallei.
Type II toxin-antitoxin (TA) systems are believed to be widely distributed amongst bacteria although their biological functions are not clear. We have identified eight candidate TA systems in the genome of the human pathogen Burkholderia pseudomallei. Five of these were located in genome islands. of the candidate toxins, BPSL0175 (RelE1) or BPSS1060 (RelE2) caused growth to cease when expressed in Escherichia coli, whereas expression of BPSS0390 (HicA) or BPSS1584 (HipA) (in an E. coli ΔhipBA background) caused a reduction in the number of culturable bacteria. The cognate antitoxins could restore growth and culturability of cells.
Abstract.
Author URL.
Full text.
Butt A, Muller C, Harmer N, Titball RW (2013). Identification of type II toxin-antitoxin modules in Burkholderia pseudomallei. FEMS Microbiology Letters, 338(1), 86-94.
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