About the Project
Antimicrobial resistance (AMR) is a major crisis for human medicine. Globally, untreatable bacterial infections are rapidly increasing, leaving us with limited treatment options. Gram-negative Enterobacteriacea such as Escherichia coli and Klebsiella pneumoniae with 3rd generation cephalosporin and carbapenem resistance are classified as critical priorities by the WHO (Tacconelli et al 2018). An important characteristic of bacteria is their ability to share genetic information, including antimicrobial resistance genes, via mobile-genetic elements such as plasmids (Carattoli 2013, Seiffert 2013, Cottell 2012, Buckner et al 2018a). Plasmids can share genes for resistance to clinically important antibiotics such as 1st, 2nd, and 3rd generation beta-lactam/cephalosporin antibiotics (the most widely used antibiotics in England (PHE 2018)), carbapenem antibiotics, and even drugs-of-last-resort e.g. colistin (Holmes et al 2016, Liu et al 2016, Douimith et al 207). Evidence indicates that clinically-relevant AMR plasmids persist in the absence of antibiotics (Cotell et al 2012, Buckner et al 2018b, Lopatkin et al 2017). Pathogens with plasmids carrying AMR genes are responsible for some of the most difficult to treat and often multi-drug resistant infections. We have developed a fluorescence-based assay to monitor plasmid dynamics in bacterial populations, and are using this assay to test anti-plasmid approaches.
Alternative approaches which target AMR plasmids will increase the longevity of our existing and new antimicrobials. This PhD project will continue work we have been doing, and will specifically address the need for complex models to examine AMR plasmid dynamics and the methods to remove AMR plasmids from bacteria within these settings. In the long term, this work has the potential to make bacteria once again susceptible to existing antibiotics.
The key aims of the project are to:
1) Develop complex models to study ARM plasmid dynamics within Gram-negative bacteria.
2) Determine the ability of anti-plasmid approaches to remove AMR plasmids from bacteria in these models.
Applicants should have a strong background in microbiology, infection, and immunology. They should have a commitment to antimicrobial resistance research and hold or realistically expect to obtain at least an Upper Second Class Honours Degree or equivalent in biology.
References
Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, Pulcini C, Kahlmeter G, Kluytmans J, Carmeli Y, Ouellette M, Outterson K, Patel J, Cavaleri M, Cox EM, Houchens CR, Grayson ML, Hansen P, Singh N, Theuretzbacher U, Magrini N. 2018. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 18:318–327.
Carrattoli A. 2013. Plasmids and the spread of resistance. Int J Med Microbiol. 303(6-7):298-304.
Seiffert SN, Hilty M, Perreten V, Endimiani A. 2013. Extended-spectrum cephalosporin-resistant Gram-negative organisms in livestock: an emerging problem for human health?Drug Resist Updat. 16(1-2):22-45.
Cottell JL, Webber MA, Piddock LJ V. 2012. Persistence of Transferable Extended-Spectrum-β-Lactamase Resistance in the Absence of Antibiotic Pressure. Antimicrob Agents Chemother 56:4703–4706.
Buckner MMC, Ciusa ML, Piddock LJ V. 2018a. Strategies to combat antimicrobial resistance: anti-plasmid and plasmid curing. FEMS Microbiol Rev 42:781–804.
Public Health England, 2018. English Surveillance Programme for Antimicrobial Utilisation and Reistance Report 2018.
Holmes AH, Moore LS, Sundsfjord A, Steinbakk M, Regmi S, Karkey A, Guerin PJ, Piddock LJ. 2016. Understanding the mechanisms and drivers of antimicrobial resistance. Lancet 387(10014):176-87.
Liu Y-Y, Wang Y, Walsh TR, Yi L-X, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu L-F, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu J-H, Shen J. 2016. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 16:161–168.
Doumith M, Findlay J, Hirani H, Hopkins KL, Livermore DM, Dodgson A, Woodford N. 2017. Major role of pKpQIL-like plasmids in the early dissemination of KPC-type carbapenemases in the UK. J Antimicrob Chemother.
Lopatkin AJ, Meredith HR, Srimani JK, Pfeiffer C, Durrett R, You L. 2017. Persistence and reversal of plasmid-mediated antibiotic resistance. Nat Commun. Nov 22;8(1):1689.
Buckner MMC, Saw HTH, Osagie RN, McNally A, Ricci V, Wand ME, Woodford N, Ivens A, Webber MA, Piddock LJV. 2018b. Clinically Relevant Plasmid-Host Interactions Indicate that Transcriptional and Not Genomic Modifications Ameliorate Fitness Costs of Klebsiella pneumoniae Carbapenemase-Carrying Plasmids. MBio 9:e02303-17.
Continue with Facebook
