Elucidating the role

The clinical management of melanoma has advanced significantly in recent years due to the development of immune and targeted therapies, transforming the clinical management of melanoma and improving patient outcomes. However, responses to these drugs are often limited and most malignant melanoma patients still die of their disease, either because they eventually develop resistance to targeted therapies or fail to respond to immunotherapies. Alterations in the PMF/ATP levels result in changes of intracellular p H, 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 Ram A can amplify the rates of antibiotic resistance development or killing in K. 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. 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 Ram A and secondly, if antibiotic challenge can also directly perturb ATP/PMF levels via intrinsic factors such as Ram A , which in turn could increase rates of mutability or reduced killing to these drugs.

Intrinsic factors that protect against antibiotic challenge are a result of evolutionary adaptation, and can be triggered as a response to cellular perturbations.Here we will study the role of SOBIR1 in LRR-RLP-mediated plant immunity, by (I) identifying its downstream interactors, (II) determining the phosphorylation status of its kinase domain in the presence or absence of the ligand matching the interacting LRR-RLP and (III) determining where SOBIR1 and LRR-RLPs interact at the subcellular level.Understanding SOBIR1 function in relation to LRR-RLP-mediated immunity provides insight into this novel and yet unexplored segment of the defence arsenal of plants and allows exploiting this regulator for generating durable and broad-spectrum resistance of plants to pathogens.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.