Biomedical Sciences

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Elucidating a role for cellular energetics in antibiotic-mediated killing of the major nosocomial pathogen K.pneumoniae

The emergence and development of antibiotic resistance is multifaceted, where mechanistically reduced drug susceptibility can occur due to the acquisition of genetic elements or via a variety of intrinsic factors that alter microbial susceptibility to a wide range of antibiotics.

Intrinsic factors that protect against antibiotic challenge are a result of evolutionary adaptation, and can be triggered as a response to cellular perturbations. The induction of these intrinsic regulatory proteins, whilst not specific for individual drugs, underscores the off-target effects of antibiotic action in bacteria. As such, we have recently shown that RamA, an intrinsic regulator of antibiotic resistance in Klebsiella pneumoniae, is induced by the biological signalling molecule indole which in turn regulates the overall electrochemical potential of the cell, thus eliciting changes in cellular energetics controlled by both the proton motive force (PMF) and ATP. Alterations in the PMF/ATP levels result in changes of intracellular pH, which impact directly on antibiotic-killing and the subsequent development of resistance. Using indole as a trigger for changes in PMF/ATP levels, we seek to determine if modulations in intrinsic proteins such as RamA can amplify the rates of antibiotic resistance development or killing in K. pneumoniae.

Thus this project aims to investigate the link between microbial cell energetics and the intrinsic adaptive response in the development of antibiotic-resistance in K. pneumoniae. Our specific aims are firstly, to establish, if alterations in ATP/PMF levels, using indole as a trigger, induce modifications to the bacterial intrinsic response to antibiotic challenge via RamA and secondly, if antibiotic challenge can also directly perturb ATP/PMF levels via intrinsic factors such as RamA , which in turn could increase rates of mutability or reduced killing to these drugs. The outcome of this work will be instrumental in providing a fundamental understanding of antibiotic action and not least in identifying novel proteins for drug development. Antibiotic resistance is a global challenge of extreme importance for our well-being. This project provides a unique opportunity to combine molecular microbiological analyses with state of the art biophysical approaches (such as single cell customized microscopy) in an interdisciplinary team spanning both Biomedical and Biological sciences.

Primary supervisor

Dr Thamarai Schneiders

Dr Thamarai Schneiders lab

thamarai.schneiders@ed.ac.uk

Second supervisor

Dr Teuta Pilizota