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Understanding Multiple Antibiotic Resistance in Gram-negative Bacteria

Principal Supervisor: Professor David Grainger, School of Biosciences

Co-supervisor: Jess Blair

PhD project title: Understanding Multiple Antibiotic Resistance in Gram-negative Bacteria.

University of Registration: University of Birmingham

Project outline:

Antibiotics have transformed medical practice, increased life expectancy and, together with vaccination, led to the near eradication of many bacterial diseases. However, overuse, including in animals, has potentiated the emergence of resistant bacteria. Such bacteria now cause millions of infections annually, with thousands of lives lost at a societal cost of billions of dollars. Moreover, the occurrence of untreatable infections is increasingly common. This disturbing trend is an immediate threat to health in every region of the world; antibiotic-resistant bacteria have the potential to affect anyone, of any age, in any country. The multiple antibiotic resistance (mar) regulon, and homologous systems, are continually implicated. Briefly, the mar operon encodes a global gene regulatory system that controls expression of genetic determinants which confer antibiotic resistance. We hypothesise that the majority of targets for MarA, and the underlying molecular mechanisms of antibiotic resistance, are undefined. This project will combine genomic tools with focused molecular biology to identify new mechanisms of antibiotic resistance and new drug targets.

References:

  1. Alekshun MN, Levy SB. (2007) Molecular mechanisms of antibacterial multidrug resistance. Cell. 128:1037-50.
  2. Blair JM, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ. (2015) Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol. 13:42-51.
  3. Sharma P, Haycocks JRJ, Middlemiss AD, Kettles RA, Sellars LE, Ricci V, Piddock LJV, Grainger DC. (2017) The multiple antibiotic resistance operon of enteric bacteria controls DNA repair and outer membrane integrity. Nat Commun. 8:1444.

BBSRC Strategic Research Priority: Sustainable Agriculture and Food: Microbial Food Safety & Understanding the Rules of Life: Microbiology & Systems Biology

Techniques that will be undertaken during the project:

Protein purification, Chromatin Immunoprecipitation, Illuminia Sequencing and associated bioinformatics, PCR, Radioisotopes, Microscopy, In vitro DNA binding assays, Reporter assays, Microbial cell culture, mutagenesis, drug uptake assays, antibiotic sensitivity assays.

Contact: Professor David Grainger, University of Birmingham