Globally, infectious disease accounts for more than 13 million deaths a year and is one of the main causes of death around the world, predominantly in developing countries. Whilst advances in public health measures and the development and use of antibiotics have led to a long term reduction in morbidity and mortality associated with many bacterial infections, the continual emergence of multi-antibiotic resistant bacteria couple with the absence of any significant progression on novel antibiotic discovery are a major threat to public health worldwide. In 2017 WHO released a “list of bacteria for which new antibiotics are urgently needed” and carbapenem-resistant/ESBL-producing Enterobacteriaceae including Klebsiella, Escherichia coli, Serratia and Proteus causing bloodstream infections and pneumonia are among the critical category. Colistin, a polymixin antibiotic, is currently used as a last-line treatment against beta-lactam resistant bacteria infections (Pharmacotherapy. 2010, 30: 1279). Until recently colistin resistance had only been observed as spontaneous chromosomal mutations, and was not transferable between bacterial cells. However, there has recently been described a plasmid born colistin resistance gene, mcr-1, which was originally found in E. coli, but which subsequently has been found in several isolates of Enterobacteriaceae from across the globe including the UK (Lancet Infect Dis 2016, 16:161).
The Mcr-1, the protein encoded by mcr-1 gene, is thought to be a membrane-anchored enzyme with phosphoethanolamine transferase activity modifying lipid A, a component of lipopolysaccharide (LPS) on Gram-negative bacterial outer membrane. LPS, also known as endotoxin, is a major virulence factor of Gram-negative bacteria which triggers strong immune responses and may lead to septic shock if present in the blood stream. The mechanism by which this modification confers resistance is still unclear, and it is not known how the expression of mcr-1 gene is regulated, nor what effects modification of LPS may have on bacterial ‘fitness’ and the ability of the bacteria to interact with the immune system and damage host cells.
1. To screen a large panel of E. coli isolates for the presence of the mcr-1 gene 2. To assess whether the presence of the gene always confers the same level of resistance to colistin 3. To investigate the physio-chemical changes to the cell surface in bacteria expressing mcr-1 4. To assess whether modification of the LPS and cell surface affects the virulence of the organisms in terms of their ability to adhere to and damage eukaryotic cells, and their induction of a host immune response