Applying New Tools to Identify Inhibitors of Antimicrobial Resistance Plasmid Transmission or Stability in Gram Negative Bacteria

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Antibiotics and antimicrobials underpin modern human and veterinary medicine. They are commonly used not only to treat infections, but also prior to surgery, and are extremely important for vulnerable patients with reduced immune function, including the young, elderly, transplant, cancer, and HIV/AIDS patients. However, the spread of multidrug resistant bacteria is rendering these treatments ineffective. The number of infections in people and animals caused by antimicrobial resistant bacteria are increasing to alarming proportions around the world, and new treatments are urgently needed. However, it has proven very difficult to find antibiotics that get inside bacteria such as E. coli, Salmonella and Pseudomonas aeruginosa (called Gram-negative bacteria). Furthermore, over the last few decades very few new antibiotics have made it to the market. Therefore, finding ways to make resistant bacteria susceptible to already existing antimicrobials is a very attractive strategy. One of the reasons antimicrobial resistance is such a growing problem is that bacteria are able to easily share their genetic information through a number of ways, including plasmid transmission. Plasmids are pieces of genetic material that can be moved from one bacterial cell to another. These plasmids often contain genes that allow bacteria to become resistant to antimicrobials (termed antimicrobial resistance genes). Therefore, bacteria are able to share antimicrobial resistance. This occurs on a global scale, with antimicrobial resistance plasmids rapidly traversing the globe, causing serious and difficult to treat infections worldwide. In this project, we will use a novel system we have developed to discover compounds that get rid of these antimicrobial resistance plasmids from bacterial populations. This could be used in a number of settings including animals, patients, farming, and waste water treatment. In animals, large quantities of antibiotics are used in a number of countries including high income countries such as the USA, which provides a platform for resistance to develop. This resistance can then spread to other nations. Our work would reduce the number of antimicrobial resistance genes in bacterial populations, therefore reducing the chances that these genes would get into human pathogens, where they could cause untreatable infections. Compounds identified in this study could also be used to clean surfaces, especially in hospitals, where antibiotic resistance is prevalent. They could also be used to eliminate antibiotic resistance genes from waste water, soil, compost, and farms. Our work could also be applied in hospitals where patients are routinely treated with antibiotics. Drugs developed from our work could be given to patients prior to antibiotic therapy, thus increasing bacteria susceptibility to antibiotics. In order to complete this work we have assembled a team of scientists with expertise in a wide range of different techniques. We will work together to provide new scientific information and knowledge crucial to combating antimicrobial resistance, by making bacteria sensitive to the antibiotics we already have available. Ultimately, this research will have a health benefit on the treatment of patients with life-threatening infections caused by antibiotic resistant bacteria.