MICA: Understanding how bacteria respond to efflux inhibition

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The number of infections in people and animals caused by antibiotic resistant bacteria are increasing to alarming proportions around the world, and new treatments are urgently needed. However, historically, it has proven very difficult to find antibiotics that can get into bacteria such as E. coli (called Gram-negative bacteria). Even when they penetrate into the cell, most get pumped out/exported (called 'effluxed'). This export is via a biological 'vacuum cleaner' that sucks substances out of the inside to the outside of the bacterial cell. A single system can transport many different types of antibiotics. Without such systems Gram-negative bacteria are killed by very low concentrations of antibiotics. The combination of restricted entry of drugs into the bacterial cell (called outer membrane permeability) and export by multidrug resistance (MDR) efflux systems are why so many antibiotics that are effective treatments for infections caused by Gram positive bacteria, such as Staphylococcus aureus, do not work against Gram negative bacteria. Efflux systems that transport antibiotics out of the cell are not only required to give antibiotic resistance but without them bacteria are unable to cause an infection or form a biofilm - a community of bacteria that live on surfaces in the host and environment. Efflux inhibitors make the bacterium very sensitive to antibiotics, make them less able to colonise or infect their hosts and less able to form a biofilm. Therefore, efflux inhibitors offer the potential to increase the effectiveness of currently available and new drugs.Our aim is to investigate the hypothesis that drug-resistant bacteria can emerge even in the presence of an efflux inhibitor. In this project, we will build upon our preliminary data by determining when E. coli becomes resistant to a combination of an antibiotic and efflux inhibitor. We will identify how the bacteria become drug resistant and find out if this type of resistance already exists in bacteria isolated from people and animals. Using a model that reproduces drug levels over time in people, we will identify ways to suppress the emergence of antibiotic and efflux inhibitor resistance.To achieve the project aim, there are two applicants, a scientist and a doctor, plus three expert collaborators from the pharmaceutical industry and two universities. We will work together to provide new scientific information and knowledge crucial to the drug discovery of efflux inhibitors. Ultimately, this research will have a health benefit on the treatment of patients with life-threatening infections caused by antibiotic resistant bacteria.