Colistin Resistance in Acinetobacter baumannii MDR-ZJ06 Revealed by a Multiomics Approach
Xiaoting Hua1, Lilin Liu1, Youhong Fang2
1Department of Infectious Diseases, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityHangzhou, China; Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang ProvinceHangzhou, China.
Abstract:
Acinetobacter baumannii has emerged as an important opportunistic pathogen due to its ability to acquire resistance to most currently available antibiotics. Colistin is often considered as the last line of therapy for infections caused by multidrug-resistant A. baumannii (MDRAB). However, colistin-resistant A. baumannii strain has recently been reported. To explore how multiple drug-resistant A. baumannii responded to colistin resistance, we compared the genomic, transcriptional and proteomic profile of A. baumannii MDR-ZJ06 to the induced colistin-resistant strain ZJ06-200P5-1. Genomic analysis showed that lpxC was inactivated by ISAba1 insertion, leading to LPS loss. Transcriptional analysis demonstrated that the colistin-resistant strain regulated its metabolism. Proteomic analysis suggested increased expression of the RND efflux pump system and down-regulation of FabZ and β-lactamase. These alterations were believed to be response to LPS loss. In summary, the lpxC mutation not only established colistin resistance but also altered global gene expression.
Insights
Multidrug-resistant Acinetobacter baumannii developed colistin resistance through an lpxC mutation, causing lipopolysaccharide loss. This genetic change triggered widespread alterations in gene expression, impacting bacterial metabolism and resistance mechanisms.
Area of Science:
- Microbiology
- Genomics
- Proteomics
Background:
- Acinetobacter baumannii is a significant opportunistic pathogen known for developing multidrug resistance.
- Colistin is a last-resort antibiotic for treating infections caused by multidrug-resistant Acinetobacter baumannii (MDRAB).
- Emergence of colistin-resistant MDRAB poses a critical threat to public health.
Purpose of the Study:
- To investigate the molecular mechanisms underlying colistin resistance in MDRAB.
- To compare the genomic, transcriptional, and proteomic profiles of a colistin-susceptible MDRAB strain with an induced colistin-resistant strain.
- To understand the global gene expression changes associated with colistin resistance.
Main Methods:
- Genomic analysis to identify genetic mutations.
- Transcriptional analysis to assess gene expression levels.
- Proteomic analysis to evaluate protein expression, focusing on efflux pumps and metabolic enzymes.
Main Results:
- Genomic analysis revealed inactivation of the lpxC gene by ISAba1 insertion in the colistin-resistant strain, leading to lipopolysaccharide (LPS) loss.
- Transcriptional analysis indicated significant metabolic regulation in the colistin-resistant strain.
- Proteomic analysis showed increased expression of the RND efflux pump system and decreased expression of FabZ and β-lactamase.
Conclusions:
- The lpxC mutation is a key factor in establishing colistin resistance in MDRAB.
- LPS loss, resulting from the lpxC mutation, drives global alterations in gene expression.
- These adaptive changes include upregulation of efflux pumps and downregulation of specific enzymes, contributing to the bacterium's resistance phenotype.
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