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Resensitization to colistin results in rapid and stable recovery of adherence, serum resistance and ompW in Acinetobacter baumannii

Boral, Jale LU orcid ; Vatansever, Cansel ; Ozcan, Gulin ; Keske, Siran ; Menekse, Sirin ; Gonen, Mehmet and Can, Fusun (2024) In PLoS ONE 19(8).
Abstract

BACKGROUND: Colistin resistance in Acinetobacter baumannii is an emerging problem that limits antimicrobial therapy options.

MATERIALS & METHODS: We isolated two pairs of colistin susceptible and colistin-resistant A. baumannii (K1007/K1006 and K408/K409) from two patients diagnosed with carbapenem-resistant A. baumannii infection. Colistin susceptible isolates were exposed to in vitro colistin induction for 50 generations. The selected cell populations were subjected to DNA and RNA sequencing and phenotypic assays.

RESULTS: In the in vitro induction assay, K408 gained colistin resistance on the corresponding day of clinical resistance (K408-G25) and got resensitized to colistin in the consecutive generation (K408-G26).... (More)

BACKGROUND: Colistin resistance in Acinetobacter baumannii is an emerging problem that limits antimicrobial therapy options.

MATERIALS & METHODS: We isolated two pairs of colistin susceptible and colistin-resistant A. baumannii (K1007/K1006 and K408/K409) from two patients diagnosed with carbapenem-resistant A. baumannii infection. Colistin susceptible isolates were exposed to in vitro colistin induction for 50 generations. The selected cell populations were subjected to DNA and RNA sequencing and phenotypic assays.

RESULTS: In the in vitro induction assay, K408 gained colistin resistance on the corresponding day of clinical resistance (K408-G25) and got resensitized to colistin in the consecutive generation (K408-G26). A significant upregulation of ompW, ata, adeFGH genes on K408-G25 was followed by a downregulation upon resensitization to colistin (G26). Despite the upregulation of the ompW gene in transcriptomic analysis, the ompW protein disappeared on K408-G25 and recovered in the resensitized generation (G26). In parallel, disrupted cell membrane integrity recovered in K408-G26. In the K408-G25, downregulation of pbpG and upregulation of pbp1a/pbp3 genes decreased serum-resistance which was reversed in the resensitized generation (G26). The K1007 did not gain colistin resistance amongst 50-generations, however, the generation corresponding to clinical resistance day (K1007-G9) had a similar trend with K408-G25. The clinical colistin-resistant K409 and K1006 had SNPs on pmrA and pmrB genes.

CONCLUSION: In this study, we observed that A. baumannii regulates adhesion, efflux pumps and serum-resistance associated genes as an early response to colistin stress. Besides, the ompW protein disappears in the cell membrane of colistin resistant cells which recovers after resensitization to colistin. The lack of ompW protein in colistin-resistant cells should be taken into consideration for escape mutants in development of antivirulence vaccination or treatment options.

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author
; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Colistin/pharmacology, Acinetobacter baumannii/drug effects, Humans, Anti-Bacterial Agents/pharmacology, Microbial Sensitivity Tests, Drug Resistance, Bacterial/genetics, Acinetobacter Infections/drug therapy, Bacterial Outer Membrane Proteins/genetics, Bacterial Adhesion/drug effects, Gene Expression Regulation, Bacterial/drug effects, Carbapenems/pharmacology
in
PLoS ONE
volume
19
issue
8
article number
e0309307
publisher
Public Library of Science (PLoS)
external identifiers
  • pmid:39196973
  • scopus:85202672388
ISSN
1932-6203
DOI
10.1371/journal.pone.0309307
language
English
LU publication?
no
additional info
Copyright: © 2024 Boral et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
id
21cf1a68-ffa6-48a8-9c7c-6c2e6630313c
date added to LUP
2024-10-28 13:08:03
date last changed
2025-08-20 05:28:46
@article{21cf1a68-ffa6-48a8-9c7c-6c2e6630313c,
  abstract     = {{<p>BACKGROUND: Colistin resistance in Acinetobacter baumannii is an emerging problem that limits antimicrobial therapy options.</p><p>MATERIALS &amp; METHODS: We isolated two pairs of colistin susceptible and colistin-resistant A. baumannii (K1007/K1006 and K408/K409) from two patients diagnosed with carbapenem-resistant A. baumannii infection. Colistin susceptible isolates were exposed to in vitro colistin induction for 50 generations. The selected cell populations were subjected to DNA and RNA sequencing and phenotypic assays.</p><p>RESULTS: In the in vitro induction assay, K408 gained colistin resistance on the corresponding day of clinical resistance (K408-G25) and got resensitized to colistin in the consecutive generation (K408-G26). A significant upregulation of ompW, ata, adeFGH genes on K408-G25 was followed by a downregulation upon resensitization to colistin (G26). Despite the upregulation of the ompW gene in transcriptomic analysis, the ompW protein disappeared on K408-G25 and recovered in the resensitized generation (G26). In parallel, disrupted cell membrane integrity recovered in K408-G26. In the K408-G25, downregulation of pbpG and upregulation of pbp1a/pbp3 genes decreased serum-resistance which was reversed in the resensitized generation (G26). The K1007 did not gain colistin resistance amongst 50-generations, however, the generation corresponding to clinical resistance day (K1007-G9) had a similar trend with K408-G25. The clinical colistin-resistant K409 and K1006 had SNPs on pmrA and pmrB genes.</p><p>CONCLUSION: In this study, we observed that A. baumannii regulates adhesion, efflux pumps and serum-resistance associated genes as an early response to colistin stress. Besides, the ompW protein disappears in the cell membrane of colistin resistant cells which recovers after resensitization to colistin. The lack of ompW protein in colistin-resistant cells should be taken into consideration for escape mutants in development of antivirulence vaccination or treatment options.</p>}},
  author       = {{Boral, Jale and Vatansever, Cansel and Ozcan, Gulin and Keske, Siran and Menekse, Sirin and Gonen, Mehmet and Can, Fusun}},
  issn         = {{1932-6203}},
  keywords     = {{Colistin/pharmacology; Acinetobacter baumannii/drug effects; Humans; Anti-Bacterial Agents/pharmacology; Microbial Sensitivity Tests; Drug Resistance, Bacterial/genetics; Acinetobacter Infections/drug therapy; Bacterial Outer Membrane Proteins/genetics; Bacterial Adhesion/drug effects; Gene Expression Regulation, Bacterial/drug effects; Carbapenems/pharmacology}},
  language     = {{eng}},
  number       = {{8}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS ONE}},
  title        = {{Resensitization to colistin results in rapid and stable recovery of adherence, serum resistance and ompW in Acinetobacter baumannii}},
  url          = {{http://dx.doi.org/10.1371/journal.pone.0309307}},
  doi          = {{10.1371/journal.pone.0309307}},
  volume       = {{19}},
  year         = {{2024}},
}