Biochemistry and Pharmacology - Research Publications
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ItemMechanisms Underlying Synergistic Killing of Polymyxin B in Combination with Cannabidiol against Acinetobacter baumannii: A Metabolomic Study(MDPI, 2022-04)Polymyxins have resurged as the last-resort antibiotics against multidrug-resistant Acinetobacter baumannii. As reports of polymyxin resistance in A. baumannii with monotherapy have become increasingly common, combination therapy is usually the only remaining treatment option. A novel and effective strategy is to combine polymyxins with non-antibiotic drugs. This study aimed to investigate, using untargeted metabolomics, the mechanisms of antibacterial killing synergy of the combination of polymyxin B with a synthetic cannabidiol against A. baumannii ATCC 19606. The antibacterial synergy of the combination against a panel of Gram-negative pathogens (Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa) was also explored using checkerboard and static time-kill assays. The polymyxin B-cannabidiol combination showed synergistic antibacterial activity in checkerboard and static time-kill assays against both polymyxin-susceptible and polymyxin-resistant isolates. The metabolomics study at 1 h demonstrated that polymyxin B monotherapy and the combination (to the greatest extent) significantly perturbed the complex interrelated metabolic pathways involved in the bacterial cell envelope biogenesis (amino sugar and nucleotide sugar metabolism, peptidoglycan, and lipopolysaccharide (LPS) biosynthesis), nucleotides (purine and pyrimidine metabolism) and peptide metabolism; notably, these pathways are key regulators of bacterial DNA and RNA biosynthesis. Intriguingly, the combination caused a major perturbation in bacterial membrane lipids (glycerophospholipids and fatty acids) compared to very minimal changes induced by monotherapies. At 4 h, polymyxin B-cannabidiol induced more pronounced effects on the abovementioned pathways compared to the minimal impact of monotherapies. This metabolomics study for the first time showed that in disorganization of the bacterial envelope formation, the DNA and RNA biosynthetic pathways were the most likely molecular mechanisms for the synergy of the combination. The study suggests the possibility of cannabidiol repositioning, in combination with polymyxins, for treatment of MDR polymyxin-resistant Gram-negative infections.
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ItemUnique mechanistic insights into pathways associated with the synergistic activity of polymyxin B and caspofungin against multidrug- resistant Klebsiella pneumoniae(ELSEVIER, 2022)Klebsiella pneumoniae is an opportunistic Gram-negative pathogen causing nosocomial infections. K. pneumoniae rapidly acquires antibiotic resistance and is known as a reservoir for resistance genes. Polymyxins remain effective as a last-line therapy against infections caused by multidrug-resistant (MDR) K. pneumoniae; however, resistance to polymyxins emerges rapidly with monotherapy. Synergistic combinations of polymyxins with FDA-approved non-antibiotics are a novel approach to preserve its efficacy whilst minimising the emergence of polymyxin resistance in K. pneumoniae. This study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with the anti-fungal caspofungin against K. pneumoniae. The combination of polymyxin B and caspofungin showed marked synergistic antibacterial killing activity in checkerboard broth microdilution and static time-kill assays at clinically relevant concentrations at early (0.5 and 1 h) and later (4 h) time points. The potential bacterial killing mechanism of the combination was studied against K. pneumoniae FADDI-KP001 using metabolomics and transcriptomics studies at 0.5, 1 and 4 h. The key pathways involved in the synergistic killing action of the combination were cell wall assembly (peptidoglycan and lipopolysaccharide biosynthesis), central carbon metabolism (glycolysis, pentose phosphate pathway and tricarboxylic acid cycle) and fatty acid biosynthesis. Moreover, the combination inhibited the most common bacterial virulence pathway (phosphotransferase system) as well as the multi-resistant efflux mechanisms, including ATP-binding cassette (ABC) transporter pathway. Overall, this study sheds light on the possibility of a polymyxin-caspofungin combination for the treatment of infections caused by K. pneumoniae and may help repurpose FDA-approved caspofungin against MDR K. pneumoniae infections.