Metabolic responses to polymyxin treatment in acinetobacter baumannii ATCC 19606: integrating transcriptomics and metabolomics with genome-scale metabolic modeling
Multidrug-resistant (MDR) Acinetobacter baumannii has emerged as a very problematic pathogen over the past decades, with a high incidence in nosocomial infections. Discovered in the late 1940s but abandoned in the 1970s, polymyxins (i.e., polymyxin B and colistin) have been revived as the last-line...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English English |
| Published: |
American Society for Microbiology
2019
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| Subjects: | |
| Online Access: | http://irep.iium.edu.my/70940/ http://irep.iium.edu.my/70940/ http://irep.iium.edu.my/70940/ http://irep.iium.edu.my/70940/7/70940_Metabolic%20Responses%20to%20Polymyxin_wos.pdf http://irep.iium.edu.my/70940/13/70940_%20Metabolic%20responses%20to%20polymyxin%20treatment%20in%20acinetobacter%20baumannii%20ATCC%2019606.pdf |
| Summary: | Multidrug-resistant (MDR) Acinetobacter baumannii has emerged as a very problematic pathogen over the past decades, with a high incidence in nosocomial infections. Discovered in the late 1940s but abandoned in the 1970s, polymyxins (i.e., polymyxin B and colistin) have been revived as the last-line therapy against Gram-negative “superbugs,” including MDR A. baumannii. Worryingly, resistance to polymyxins in A. baumannii has been increasingly reported, urging the development of novel antimicrobial therapies to rescue this last-line class of antibiotics. In the present study, we integrated genome-scale metabolic modeling with multiomics
data to elucidate the mechanisms of cellular responses to colistin treatment in A.
baumannii. A genome-scale metabolic model, iATCC19606, was constructed for strain
ATCC 19606 based on the literature and genome annotation, containing 897 genes,
1,270 reactions, and 1,180 metabolites. After extensive curation, prediction of growth
on 190 carbon sources using iATCC19606 achieved an overall accuracy of 84.3%
compared to Biolog experimental results. Prediction of gene essentiality reached a
high accuracy of 86.1% and 82.7% compared to two transposon mutant libraries of
AB5075 and ATCC 17978, respectively. Further integrative modeling with our correlative
transcriptomics and metabolomics data deciphered the complex regulation on
metabolic responses to colistin treatment, including (i) upregulated fluxes through
gluconeogenesis, the pentose phosphate pathway, and amino acid and nucleotide
biosynthesis; (ii) downregulated TCA cycle and peptidoglycan and lipopolysaccharide
biogenesis; and (iii) altered fluxes over respiratory chain. Our results elucidated the interplay
of multiple metabolic pathways under colistin treatment in A. baumannii and
provide key mechanistic insights into optimizing polymyxin combination therapy. |
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