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Comparative Study
. 2018 Feb 23;8(1):3515.
doi: 10.1038/s41598-018-21841-9.

Comparative transcriptomics of multidrug-resistant Acinetobacter baumannii in response to antibiotic treatments

Hao Qin  1   2   3 , Norman Wai-Sing Lo  4 , Jacky Loo  1 , Xiao Lin  1   2 , Aldrin Kay-Yuen Yim  1   2   5 , Stephen Kwok-Wing Tsui  6 , Terrence Chi-Kong Lau  7 , Margaret Ip  4 , Ting-Fung Chan  8   9
Affiliations
Comparative Study

Comparative transcriptomics of multidrug-resistant Acinetobacter baumannii in response to antibiotic treatments

Hao Qin et al. Sci Rep. .

Abstract

Multidrug-resistant Acinetobacter baumannii, a major hospital-acquired pathogen, is a serious health threat and poses a great challenge to healthcare providers. Although there have been many genomic studies on the evolution and antibiotic resistance of this species, there have been very limited transcriptome studies on its responses to antibiotics. We conducted a comparative transcriptomic study on 12 strains with different growth rates and antibiotic resistance profiles, including 3 fast-growing pan-drug-resistant strains, under separate treatment with 3 antibiotics, namely amikacin, imipenem, and meropenem. We performed deep sequencing using a strand-specific RNA-sequencing protocol, and used de novo transcriptome assembly to analyze gene expression in the form of polycistronic transcripts. Our results indicated that genes associated with transposable elements generally showed higher levels of expression under antibiotic-treated conditions, and many of these transposon-associated genes have previously been linked to drug resistance. Using co-expressed transposon genes as markers, we further identified and experimentally validated two novel genes of which overexpression conferred significant increases in amikacin resistance. To the best of our knowledge, this study represents the first comparative transcriptomic analysis of multidrug-resistant A. baumannii under different antibiotic treatments, and revealed a new relationship between transposons and antibiotic resistance.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Fast-growing pan-drug-resistant strains exhibited higher nutrition uptake and utilization ability. (a) Phylogenetic tree including collected strains and 15 published complete genomes. (b) Growth curves of 12 strains in BHI broth over 5 hours. Error bars: standard error. p-values were calculated by Student’s t-test. (c) Heat map of differentially expressed genes between fast-growing strains and slow-growing strains, classified by functional groups.
Figure 2
Figure 2
Genes that were differentially expressed under antibiotic treatment. Red genes or arrows: genes that were consistently up-regulated under treatment with all three antibiotics. Purple genes or arrows: genes that were consistently up-regulated only under treatment with amikacin. Green genes or arrows: genes that were consistently down-regulated only under treatment with the two carbapenem-related antibiotics.
Figure 3
Figure 3
Antibiotic resistance genes were widely distributed in resistant and sensitive strains. Each square represents the expression level of a gene (across the row) in a given strain (down the column). Genes are grouped according to protein functions, followed by the type of antibiotic resistance that the gene is associated with.
Figure 4
Figure 4
Transposons were up-regulated in multidrug-resistant strains and their associated genes maintained relatively higher expression in antibiotic-treated environments. (a) Statistics of genes co-transcribed with known antibiotic resistance genes. (b) Heat map of differentially expressed genes between multidrug-resistant strains and -sensitive strains, classified by functional groups. (c–e) Comparison of percentile-of-expression values between transposon-associated genes and non-transposon-associated genes at antibiotic-free mid-log phase (c), antibiotic-treated mid-log phase (d), and antibiotic-treated stationary phase (e). Blue line represents transposon-associated genes; red line represents non-transposon-associated genes. p-values were calculated by Wilcoxon’s rank-sum test. (f) Boxplots of fold changes of known antibiotic resistance genes under the antibiotic treatments. Each point represents a log(fold change) value of a known antibiotic resistance gene under a certain antibiotic treatment. p-values were calculated by Wilcoxon’s rank-sum test.
Figure 5
Figure 5
Identification of novel antibiotic-specific resistance genes. Each square represents the expression level or the presence of a gene (down the column) in a given strain (across the row). The resistance of each strain to the three antibiotics is shown on the right panel.
Figure 6
Figure 6
Transposon-associated mel and mph were co-transcribed and both contributed to amikacin resistance. (a) Transcript structure of the transposon gene with the two candidates. (b) Reverse-transcription PCR result of connection regions among three genes (mel, mph, and tnpD). (c) Quantitative PCR results for those three genes. (d) Growth of E. coli transformed with the two candidate genes (mel and mph) in different amikacin concentrations.
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