About the Project
Neisseria meningitidis (the meningococcus) is a leading global cause of meningitis and septicaemia. With the exception of the sulphonamides, high-level antimicrobial resistance is rare in meningococci. Penicillin remains the therapeutic drug of choice where microbiologically indicated, while ciprofloxacin is commonly used in prophylaxis to clear nasopharyngeal carriage in patients and their contacts. The frequency of isolates displaying intermediate resistance to penicillin has increased over several decades and, more recently, raised MICs for 3rd generation cephalosporins have been reported. Reduced sensitivity to these compounds is often a result of recombination between the meningococcal penA gene (encoding penicillin-binding protein 2) and those of commensal Neisseriae or Neisseria gonorrhoeae. Ciprofloxacin resistance due to altered gyrA alleles (encoding DNA gyrase), although rare, has also been observed in diverse isolates with point mutation and/or interspecies recombination as possible origins.
In collaboration with the Public Health England Meningococcal Reference Unit, this PhD project will examine genome sequences from isolates derived from confirmed invasive meningococcal disease (IMD) cases and correlate them with degrees of resistance to penicillin, ciprofloxacin and cefotaxime, as well as other phenotypic data. Resistance of selected strains to particular antibiotics will also be induced in the laboratory, and genome sequences from the resulting strains compared with those found from IMD cases. The project will illuminate how horizontal genetic exchange contributes to the spread of antibiotic resistance in an important human pathogen.
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with experience in Microbiology or a related subject are encouraged to apply.
Funding Notes
This project has a Band 2 fee. Details of our different fee bands can be found on our website (https://www.bmh.manchester.ac.uk/study/research/fees/). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/).
Informal enquiries may be made directly to the primary supervisor, Professor James McInerney ([Email Address Removed]).
References
1. Bijlsma MW, Bekker V, Brouwer MC, Spanjaard L, van de Beek D, van der Ende A. Epidemiology of invasive meningococcal disease in the Netherlands, 1960-2012: an analysis of national surveillance data. Lancet Infect Dis. 2014 Sep;14(9):805-12.doi: 10.1016/S1473-3099(14)70806-0. PubMed PMID: 25104306.
2. Bowler LD, Zhang QY, Riou JY et al. Interspecies recombination between the penA genes of Neisseria meningitidis and commensal Neisseria species during the emergence of penicillin resistance in N. meningitidis: natural events and laboratory simulation. J Bacteriol 1994; 176: 333–7.
3. Spratt BG, Bowler LD, Zhang QY et al. Role of interspecies transfer of chromosomal genes in the evolution of penicillin resistance in pathogenic and commensal Neisseria species. J Mol Evol 1992; 34: 115–25.
4. Deghmane AE, Hong E, Taha MK. Emergence of meningococci with reduced susceptibility to third-generation cephalosporins. J Antimicrob Chemother. 2017 Jan;72(1):95-98
5. Hong E, Thulin Hedberg S, Abad R, Fazio C, Enríquez R, Deghmane AE, Jolley KA, Stefanelli P, Unemo M, Vazquez JA, Veyrier FJ, Taha MK. Target gene sequencing to define the susceptibility of Neisseria meningitidis to ciprofloxacin. Antimicrob Agents Chemother. 2013 Apr;57(4):1961-4. doi: 10.1128/AAC.02184-12. PubMed PMID: 23357770; PubMed Central PMCID: PMC3623314.
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