Deciphering the modes of action of polymyxins and the synergistic combinations against multidrug-resistant Gram-negative bacteria: a systems pharmacology approach

Multidrug-resistant Gram-negative bacteria, particularly Acinetobacter baumannii and Pseudomonas aeruginosa present a significant threat to human health globally and polymyxins are increasingly used as the last-line defence. Polymyxin combination therapy has been strongly recommended, as pharmacokinetic/pharmacodynamic studies reveal that polymyxins often fail to achieve an effective exposure in vivo which potentially leads to the emergence of resistance. This thesis provides much-needed mechanistic insights into polymyxin action and synergistic combinations with other antibiotics using metabolomics and transcriptomics. This study highlights the significant potential of paradigm-shifting systems pharmacology in optimising antibiotic use. Overall, this project targets the urgent global medical challenge, antibiotic resistance.