TY - JOUR
T1 - Mechanisms Underlying Synergistic Killing of Polymyxin B in Combination with Cannabidiol against Acinetobacter baumannii
T2 - A Metabolomic Study
AU - Hussein, Maytham
AU - Allobawi, Rafah
AU - Levou, Irini
AU - Blaskovich, Mark A.T.
AU - Rao, Gauri G.
AU - Li, Jian
AU - Velkov, Tony
N1 - Funding Information:
Acknowledgments: This research was supported by a research grant from the National Institute of Allergy and Infectious Diseases of the National Institute of Health (R01 AI146241, GR, and TV). JL is an Australian National Health Medical Research Council (NHMRC) Principal Research Fellow. J.L. is an Australian National Health and Medical Research Council (NHMRC) Principal Research Fellow, and T.V. is an Australian NHMRC Industry Career Development Level 2 Research Fellow. The content is solely the authors’ responsibility and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institute of Health.
Funding Information:
G.G.R.: T.V. and J.L. are supported by the National Institute of Allergy and Infectious Diseases, award number R01AI146241. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This research was supported by a research grant from the National Institute of Allergy and Infectious Diseases of the National Institute of Health (R01 AI146241, GR, and TV). JL is an Australian National Health Medical Research Council (NHMRC) Principal Research Fellow. J.L. is an Australian National Health and Medical Research Council (NHMRC) Principal Research Fellow, and T.V. is an Australian NHMRC Industry Career Development Level 2 Research Fellow. The content is solely the authors? responsibility and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institute of Health.
Funding Information:
Funding: G.G.R.: T.V. and J.L. are supported by the National Institute of Allergy and Infectious Diseases, award number R01AI146241. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
KW - antimicrobial peptides
KW - antimicrobial resistance
KW - cannabidiol
KW - MDR Gram-negative
KW - metabolomics
UR - http://www.scopus.com/inward/record.url?scp=85128460021&partnerID=8YFLogxK
U2 - 10.3390/pharmaceutics14040786
DO - 10.3390/pharmaceutics14040786
M3 - Article
C2 - 35456620
AN - SCOPUS:85128460021
SN - 1999-4923
VL - 14
JO - Pharmaceutics
JF - Pharmaceutics
IS - 4
M1 - 786
ER -