Fundamental Biophysical Study of the Antimicrobial Properties of Nisin for the Development of Novel Antibiotics

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Antimicrobial resistance is an avoidable global and economic health threat, projected to be responsible for 10 million deaths per annum by 2050. Nisin is a polycyclic antimicrobial peptide which is active against multi-drug resistant strains of bacteria and non-toxic to humans, and has low resistance rates. Although Nisin demonstrates promising therapeutic potential, its mechanism of action remains poorly understood. Hence, there is a need to advance biophysical methodology and develop more effective chemical tools to probe Nisin's antimicrobial mode of action. Currently, it is understood that Nisin exhibits a dual mode of action, based on either sequestration of Lipid II, a key chemical involved in bacterial cell regulation, or nanopore formation to disrupt vital cell ion gradients. The latter hypothesis lacks, however, detailed characterization of nanopores. Research questions relate to the size, surface charges and stability of the nanopores, their kinetics of formation, and possible ion specificity. These questions will be addressed in the PhD project via electrophysiological techniques which have never been used for Nisin including pore sizing with polymers and ion flux measurements. In addition, thermodynamic methods such as isothermal titration will be applied to understand the membrane binding and multimerization mechanism. The newly gained biophysical insight will guide the structure-activity based organic synthesis of modern peptide therapeutics. By facilitating development of a new generation of antibiotics, our approach has the potential to benefit the pharmaceutical industry and global healthcare.