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Virulence

ISSN: 2150-5594 (Print) 2150-5608 (Online) Journal homepage: https://www.tandfonline.com/loi/kvir20

The effect of ISAba1-mediated adeN gene
disruption on Acinetobacter baumannii
pathogenesis

Man Hwan Oh, Chul Hee Choi & Je Chul Lee

To cite this article: Man Hwan Oh, Chul Hee Choi & Je Chul Lee (2017) The effect of ISAba1-
mediated adeN gene disruption on Acinetobacter_xFFFF_baumannii pathogenesis, Virulence, 8:7,
1088-1090, DOI: 10.1080/21505594.2017.1339859

To link to this article: https://doi.org/10.1080/21505594.2017.1339859

© 2017 Taylor & Francis

Published online: 13 Jul 2017.

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VIRULENCE
2017, VOL. 8, NO. 7, 1088–1090
https://doi.org/10.1080/21505594.2017.1339859

EDITORIAL

The effect of ISAba1-mediated adeN gene disruption on Acinetobacter
baumannii pathogenesis

Man Hwan Oha, Chul Hee Choib, and Je Chul Leec

aDepartment of Nanobiomedical Science, Dankook University, Cheonan, South Korea; bDepartment of Microbiology and Medical Sciences,
Chungnam National University, School of Medicine, Daejeon, South Korea; cDepartment of Microbiology, Kyungpook National University School
of Medicine, Daegu, South Korea

ARTICLE HISTORY Received 2 June 2017; Accepted 2 June 2017

KEYWORDS Acinetobacter baumannii; insertion sequence; RND efflux system; transcription regulator; virulence

independent

In many pathogenic bacteria, mobile genetic elements
such as integrons, transposons, and insertion sequence
(IS) elements play important roles in genome plasticity
and genetic variability.1 IS elements are the simplest
mobile genetic element and are widespread in bacterial
genomes.2 They contain coding regions for proteins
transposition, as well as
required for
inverted repeats on both sides. IS element transposition
is responsible for the insertion of one DNA sequence
into another, and is considered one of the major bacterial
DNA rearrangements through which changes in gene
expression occur.3 IS element transposition can inacti-
vate gene products through the insertion of IS elements
within a targeted gene. This gene inactivation is respon-
sible for changes in bacterial metabolism, antimicrobial
resistance, and virulence.4 IS element transposition is
also able to create an alternative target gene promoter
through which the target gene is activated. Consequently,
the transposition of IS elements enables bacteria to over-
come new environmental challenges and adapt to new
environmental niches. The IS element-mediated hori-
zontal transfer of antimicrobial resistance genes contrib-
utes to the prevalence of multidrug-resistant (MDR)
Acinetobacter baumannii,5,6 an important opportunistic
pathogen responsible for nosocomial infection particu-
larly in severely ill patients.7,8 ISAba1, ISAba2, ISAba3,
ISAba4, ISAba125, and ISAba825 are IS elements associ-
ated with antimicrobial resistance in A. baumannii.5
ISAba1 is the most common IS element, responsible for
the expression of antimicrobial resistance genes such as
AmpC in A. bauman-
bla
nii.5,6 ISAba1 has been found in the upstream region of
resistance genes, acting as a promoter to significantly

OXA-51-like, and bla

OXA-23-like, bla

increase their expression.9 It has been shown that
ISAba1-mediated disruption of global repressors such as
histone-like nucleoid-structuring (H-NS) protein is
responsible for elevated virulence in A. baumannii.10
However, the individual factors determining the elevated
virulence of clinical A. baumannii isolates have been
poorly characterized, despite their clinical significance.

In this issue of Virulence, Saranathan et al11 analyzed
the genome of a hyper-virulent, MDR A. baumannii
PKAB07 strain isolated from an Indian patient to under-
stand the genetic factors contributing to its elevated viru-
lence, and studied the importance of adeN in its
pathogenesis. The authors found one gene segment
encoding 23 open reading frames (ORFs) in the PKAB07
genome. These ORFs include coding sequences for vari-
ous genes such as TetR family transcriptional regulators,
through which transportation of antimicrobial agents,
small molecules, and toxins is facilitated.12 This gene seg-
ment was also found among the MDR A. baumannii
clonal complex 92, a subgroup of international clonal
lineage II. The authors suggest that this could play an
important role in the global spread of this clone. It was
also found that genes encoding transcription regulator
(AdeN), cAMP binding protein, TonB-dependent side-
rophore receptor, putative outer membrane protein, a
hypothetical protein, dehydrogenase with different spe-
cificities, and putative dehydrogenase are inactivated by
the insertion of ISAba1. Based on previous studies dem-
onstrating the role of resistance-nodulation-cell division
(RND)-type efflux systems on antimicrobial resistance
and virulence of A. baumannii strains,13,14 the authors
were interested in ISAba1 insertion into adeN, a gene
the
encoding a TetR-type regulator

represses

that

leejc@knu.ac.kr

CONTACT Je Chul Lee
Daegu 41944, Republic of Korea.
Comment on: Saranathan R, et al. Disruption Disruption of tetR type regulator adeN by mobile genetic element confers elevated virulence in Acinetobacter
baumannii. Virulence 2017 [in press]; https://doi.org/10.1080/21505594.2017.1322240
© 2017 Taylor & Francis

Department of Microbiology, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Jung-gu,

pathogenesis,

expression of the adeIJK gene cluster, which encodes a
3-component RND efflux system composed of a peri-
plasmic membrane fusion protein (AdeI), an inner mem-
brane RND transporter (AdeJ), and an outer membrane
factor (AdeK). TetR-type regulators are mainly tran-
scriptional repressors through which antimicrobial resis-
and
bacterial
tance, metabolism,
responses are regulated.12 To
environmental
stress
explore the effects of ISAba1-mediated adeN inactivation
on A. baumannii pathogenesis, adeN mutation and adeN
complementation were conducted in A. baumannii
ATCC 17978 through allelic exchange. The authors
ISAba1-mediated adeN inactivation in
showed that
PKAB07 and adeN knockout in ATCC 17978 eliminate
the transcriptional repression of adeIJK. These results
were further validated by the elevated resistance of
PKAB07 and DadeN mutant of ATCC 17978 to multiple
antimicrobial agents that are likely substrates of the
AdeIJK efflux system. The AdeIJK efflux system is
detected in all A. baumannii strains and contributes to
intrinsic low level resistance to various antimicrobial
agents, including b-lactams, chloramphenicol, tetracy-
lincosamides, fluoroquinolones,
clines, erythromycin,
rifampin, trimethoprim, novobiocin, and fusidic acid.13
However, overexpression of adeIJK was shown to be
toxic in Escherichia coli and Acinetobacter species,13 indi-
cating that the expression of this gene cluster is tightly
regulated. AdeN acts as a repressor of the adeIJK operon
in A. baumannii strains.14 The previous study indicated
that deletion of adeN in A. baumannii is responsible for
diminished susceptibility to AdeIJK substrates such as
erythromycin, chloramphenicol, tetracycline, b-lactams,
sulfonamides, and quinolones.14 However, natural over-
expression of adeIJK is implausible when considering a
threshold for toxicity. It is therefore reasonable to con-
clude that insertional inactivation of adeN by ISAba1,
which is likely to be lethal to A. baumannii because of
adeIJK overexpression, is slowly evolving an intrinsic
low level expression of adeIJK genes tolerable to A. bau-
mannii. This is the first published observation of natu-
rally inactivated adeN in A. baumannii. Saranathan et
al11 showed the characteristics of A. baumannii pathoge-
nicity resulting from insertional inactivation of adeN by
ISAba1 experimentally. In comparison with the ATCC
17978 wild-type, the ability of DadeN mutant to produce
biofilm was significantly reduced. Based on this result,
the authors suggest that AdeN may be a positive regula-
tor of biofilm formation in A. baumannii. However,
upon co-cultivation with human alveolar epithelial A549
cells, PKAB07 and DadeN mutant of ATCC 17978, but
not the wild-type strain, significantly reduced the viabil-
ity of A549 cells, indicating that the inactivation of adeN
results in a substantial increase in their virulence. The

VIRULENCE

1089

negative correlation between biofilm formation and viru-
lence in PKAB07 is interesting, since biofilm formation
in A. baumannii is closely linked to its pathogenesis, and
to its survival in clinical environments, which are prone
to unfavorable conditions such as nutrient limitation,
desiccation, and antimicrobial treatment. It was reported
that the modulated adeIJK expression is responsible for
under-expression of CsuA/B/C and FimA, which are
required for chaperone-usher pilus assembly systems, a
major factor in A. baumannii biofilm formation.15 It is
thus possible that inactivation of adeN and subsequent
overexpression of adeIJK may result in the under-expres-
sion of CsuA/B/C and FimA, leading to a reduction in
PKAB07 biofilm formation. Galleria mellonella larvae
has been used to assess the virulence of A. baumannii
strains owing to the positive correlation between their
virulence in mice and G. mellonella larvae.16,17 The effect
of adeN mutation on the virulence of A. baumannii was
evaluated by monitoring the mortality of the larvae
infected with the A. baumannii strains. PKAB07 and
DadeN mutant were shown to be more virulent and led
to increased larval mortality than the ATCC 17978
strain.
It was shown that AdeIJK derepression by
inactivation of adeN contributes to the virulence of
A. baumannii in G. mellonella.18 It is reasonable to sug-
gest that the overexpression of adeIJK resulting from
adeN inactivation could provide A. baumannii with a
defense against the G. mellonella larval immune system.
The article entitled “Disruption of tetR type regulator
adeN by mobile genetic element confers elevated viru-
lence in Acinetobacter baumannii”11 described for the
first
time that adeN is naturally disrupted by the
insertion of ISAba1 in A. baumannii. This study is
noteworthy because the authors have shown the effects
of ISAba1-meidated adeN disruption on A. baumannii
pathogenesis, highlighting adeN as a potential target
for monitoring
emergence of hyper-virulent
the
A. baumannii strains.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

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