Colistin Resistance in Acinetobacter baumannii MDR-ZJ06 Revealed by a Multiomics Approach

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.

Comprehensive proteomic and metabolomic profiling of mcr-1 mediated colistin resistance in Escherichia coli

“…Our findings demonstrated colistin and polymyxin B made mcr-1 -mediated resistant bacteria to exhibit different proteome profiles and it suggest that colistin-resistant bacteria might alter their metabolism to adapt to antibiotic resistance (Fig 1D). Proteomic characteristics discovered by SWATH-MS showed that mcr-1 could cause the disturbed metabolic regulation such as glycerophospholipid metabolism, thiamine metabolism, LPS biosynthesis, and CAMP resistance (Fig 3) and the protein profile of E. coli carrying mcr-1 to colistin showed the most significant changes, which was consistent with the report of Hua et al [24]. Integrative proteomic and metabolomic analysis demonstrated that GlpQ, EutE involved in glycerphospholipid metabolism were significantly up-regulated in colistin-resistant E. coli DH5α (pUC19- mcr-1 ) under the condition of blank LB broth.…”

“…It was noteworthy that the fatty acyl side chains with the C 12 -C 14 carbon chain of the lipid A group, which was essential for the maintenance of bacterial LPS function, were involved in the synthesis of bacterial fatty acid type II synthesis pathway, suggesting that it was essential to decipher the metabolic mechanism of mcr-1 mediated resistance from a metabolic perspective. Hua et al [24] utilized a multiomics approach to explore the response of multiple drug-resistant A. baumannii to colistin and found that RND efflux pump system were over-expressed and inhibited the expression of FabZ and β-lactamase. However, as a lipid-modified gene, the comprehensive proteomic and metabolomic profiling of mcr-1 -mediated colistin resistance in bacteria is still unknown.…”

<p>Discovery of a Novel Hypervirulent <em>Acinetobacter baumannii</em> Strain in a Case of Community-Acquired Pneumonia</p>

“…Whole genome sequencing (WGS) by Hiseq (Illumina, Carlsbad, CA) were performed as described previously. 8 Bacteria from a single colony were cultured overnight at 37°C in MH broth. The genomic DNA was extracted via a QIAamp DNA minikit (Qiagen, Valencia, CA, USA) following the protocol of the manufacturer's protocol.…”

“…2 Although both tigecycline and colistin have been used effectively in the treatment of A. baumannii previously, resistant isolates have been reported. 7,8 While traditionally associated with nosocomial infections, A. baumannii is more frequently attributed to community-acquired pneumonia (CAP) in tropical and sub-tropical climates. 4,9,10 Although CAP strains are typically more susceptible to antibiotics than strains implicated in hospital acquired infections (HAI), CAP caused by A. baumanni is characterized by a fulminant and severe infection with high mortality.…”

Adaptation of Acinetobacter baumannii to colistin exposure: Laboratory mimicking of a clinical case

“…Exposure to colistin is considered as the most significant factor for emerging of colistin resistance (2), however, details of the in vivo response of A. baumannii to colistin exposure, such as the number of days for development of resistance was not described. The molecular studies about colistin resistance indicated two main mechanisms: modifications in lipid A structure and complete loss of LPS (3). By this study, we analyzed adaptation of A. baumannii to colistin use on a disease course of a patient.…”