Mode of action study for a novel class of antimicrobial polymers against methicillin-resistant Staphylococcus aureus

• Main Author: Shi, Zhenyu
• Other Authors: Chan Bee Eng, Mary
• Format: Thesis-Master by Research
• Language: English
• Published: Nanyang Technological University 2020
• Subjects: Engineering::Bioengineering; Science::Biological sciences::Microbiology::Bacteria
• Online Access: https://hdl.handle.net/10356/136786
• Institution: Nanyang Technological University

The development of antibiotics has been hampered by the rapid evolution of antimicrobial resistance and lack of new mechanisms discovered. Membrane- polarizing cationic polymers have attracted attention due to their low propensity to induce resistance. A cationic polymer (labelled as PIM1) has been found to exert excellent antimicrobial efficacy with low cell toxicity. To understand the mechanism of action of PIM1, investigations were carried out in methicillin- resistant Staphylococcus aureus (MRSA). It was found that PIM1 had a distinctively different mechanism from common cationic polymers, since it did not physically disrupt and perforate the cytoplasmic membrane. Instead, the polymer blocked aerobic respiration, leading to pleiotropic effects on multiple biosynthetic pathways in the bacteria. Whole genome sequencing of PIM1- resistant MRSA strains revealed that genes associated with bacteria surface charge and the electron transport chain (ETC) were crucial for the activity of PIM1. Studies with respiratory mutants implied a strong relationship between the level of aerobic respiration and the efficacy of PIM1. Moreover, PIM1 was found to decrease the intracellular menaquinone content at sub-inhibitory concentrations, suggesting a direct interaction between PIM1 and the ETC component menaquinone. The results suggest that PIM1 binds to the bacteria surface through electrostatic attraction, and interact with the membrane-bound ETC which leads to cell death.