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Biophysical techniques applied to bacterial resistance

Abstract

Since most of the adverse effects are dose-related, ²-lactams have been the drug of choice for the treatment of bacterial infection. However, the misuse of these antimicrobial drugs speeded up the emergence of drug-resistant bacteria. It is important to emphasize that 9 of the 12 most dangerous families of bacteria, data released by WHO, has the presence of ²-lactamase as the main mechanism of resistance. On top of that list is Acinetobacter baumannii, an opportunistic pathogen whose prime mechanism of resistance are the Carbapenem Hydrolyzing Class D ²-lactamases (CHDLs). These enzymes are recently evolved variants of oxacillinases (OXAs) and are capable of conferring carbapenem resistance to this bacterium. Furthermore, results involving CHDLs demonstrate that structure is not playing alone, and evolution may have selected for protein dynamics as well as structure. Therefore, understand the evolutionary pathway that leads to improved ²-lactamases is mandatory for the discovery of new antibiotics.The aim of this proposal is to study structural and mechanistic aspects of the Class D ²-lactamases using biophysical techniques such as Nuclear Magnetic Resonance (NMR), Isothermal Titration Calorimetry (ITC), and Molecular Dynamics (MD). Additionally, we aim to comprehend why some mutations lead to a broad spectrum of activity, such as P227S, while others lead to a convergence towards a more specific subclass of ²-lactams. Finally, understand how Class D ²-lactamases are evolving to "prevent" product inhibition. It is expected that these studies will contribute to a better understanding of the biology and pathogenesis of bacteria carrying the blaOXA gene, and hence, to the development of antibiotics/inhibitors compounds in the future. (AU)

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