Structural basis of novel strategies for the inhibition of AmpC-mediated beta-lactam antibiotic resistance in the opportunistic, nosocomial pathogen Pseudomonas aeruginosa
Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen often responsible for hospital-acquired infections, which can be very difficult to treat due to antibiotic resistance. A common mechanism of resistance is the expression of beta-lactamase enzymes, which break down and disarm classical beta-lactam antibiotics, such as penicillins. Beta-lactam antibiotics act by breaking down the bacterial cell wall, producing cell wall fragments that induce expression of the beta-lactamase, AmpC. In many Gram-negative bacteria, AmpC base expression is low but can be induced by exposure to beta-lactams. Current beta-lactamase inhibitors are ineffective against AmpC, therefore blocking upregulation is a potential strategy to combat the resistance effects. AmpG, a transporter that imports the cell wall fragments needed for AmpC expression, is an exciting new target. This project aims to solve the first atomic resolution structure of AmpG and further our understanding of how the transporter functions. This project has the potential to translate directly into the development of new AmpG inhibitors and treatment strategies that preserve the effectiveness of current antibiotic therapeutics in the clinic and community.