- 作者: Mohd Hafidz Mahamad Maifiah, Yan Zhu, Brian T. Tsuji, Darren J. Creek, Tony Velkov & Jian Li
- 作者服務機構: 1.Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, VIC, 3010, Australia 2.Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA 3.Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia 4.Infection Program and Department of Microbiology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia 5.International Institute for Halal Research and Training, International Islamic University Malaysia, 50728, Kuala Lumpur, Malaysia
- 中文摘要:
- 英文摘要:
Background: Understanding the mechanism of antimicrobial action is critical for improving antibiotic therapy. For
the frst time, we integrated correlative metabolomics and transcriptomics of Pseudomonas aeruginosa to elucidate
the mechanism of synergistic killing of polymyxin–rifampicin combination.
Methods: Liquid chromatography-mass spectrometry and RNA-seq analyses were conducted to identify the signifcant changes in the metabolome and transcriptome of P. aeruginosa PAO1 after exposure to polymyxin B (1 mg/L)
and rifampicin (2 mg/L) alone, or in combination over 24 h. A genome-scale metabolic network was employed for
integrative analysis.
Results: In the frst 4-h treatment, polymyxin B monotherapy induced signifcant lipid perturbations, predominantly
to fatty acids and glycerophospholipids, indicating a substantial disorganization of the bacterial outer membrane.
Expression of ParRS, a two-component regulatory system involved in polymyxin resistance, was increased by polymyxin B alone. Rifampicin alone caused marginal metabolic perturbations but signifcantly afected gene expression
at 24 h. The combination decreased the gene expression of quorum sensing regulated virulence factors at 1 h (e.g.
key genes involved in phenazine biosynthesis, secretion system and bioflm formation); and increased the expression
of peptidoglycan biosynthesis genes at 4 h. Notably, the combination caused substantial accumulation of nucleotides
and amino acids that last at least 4 h, indicating that bacterial cells were in a state of metabolic arrest.
Conclusion: This study underscores the substantial potential of integrative systems pharmacology to determine
mechanisms of synergistic bacterial killing by antibiotic combinations, which will help optimize their use in patients. - 中文關鍵字:
- 英文關鍵字: Gram-negative bacteria, Antibiotic resistance, Combination therapy, Systems pharmacology, Colistin, Genome-scale metabolic modeling