Targeting Efflux Pumps to Combat Antimicrobial Resistance

Antibiotic resistance is currently one of the gravest threats to global public health and economic development, estimated to cause an additional 10 million deaths per year and a loss of up to US$100 trillion from the global economy by 2050. Bacteria can become resistant to antibiotics in many ways but one important mechanism is through the action of multi-drug efflux pumps. These pumps are located in the bacterial cell membrane and function to pump antibiotics out of cells. This reduces intracellular concentration of drug within bacteria allowing them to survive at higher drug concentrations and therefore, conferring antibiotic resistance. Many efflux pumps can export multiple classes of antibiotic so the bacteria are resistant to many drugs at the same time, known as multi-drug resistance (MDR).
The resistance-nodulation-division (RND) family of efflux pumps confer antibiotic resistance to many human and animal pathogens, including the foodborne pathogen Salmonella. In Salmonella, the major efflux pump of this family, AcrB, confers antibiotic resistance and is commonly over-expressed in multi-drug resistant (MDR) clinical and veterinary isolates. RND pumps, including AcrB, are organized as tri-partite systems, consisting of an inner membrane efflux transporter, a periplasmic adaptor protein (PAP) and an outer membrane channel.
Previous studies have shown that PAPs are a good target for development of efflux inhibitors. If an appropriate inhibitor of PAPs was identified, it could be employed in tandem with an existing antibiotic to restore susceptibility to that antibiotic and prevent the recurrence of resistance. Therefore, this project will aim to develop/identify potential inhibitor molecules of the PAPs.