Izabela Kern-Zdanowicz Załącznik nr 3 Autoreferat w jęz. angielskim 1 SUMMARY OF PROFESSIONAL ACCOMPLISHMENTS 1. Name Izabela Maria Kern-Zdanowicz 2. Education and obtained scientific titles 1997 – Doctor of Philosophy degree biochemistry Institute of Biochemistry and Biophysics Polish Academy of Sciences PhD thesis titled: „Secretion of streptokinase of Streptococcus equisimilis H46A in bacterial homologous and heterologous systems, Supervisor: Piotr Cegłowski D. Sc. Ph. D. 1986 – Master of Science title in biology/ specialization: molecular biology, Faculty of Biology, University of Warsaw; Supervisor: prof. Ewa Bartnik 3. Employment in scientific institutions 2007 – till now employment as a research assistant in the Institute of Biochemistry and Biophysics Polish Academy of Sciences in Warsaw, 1997 – 2007 employment as a research adjunct in the Institute of Biochemistry and Biophysics Polish Academy of Sciences in Warsaw, 1992 – 1997 employment as a research assistant in the Institute of Biochemistry and Biophysics Polish Academy of Sciences in Warsaw, 1990 – 1992 employment as a research assistant in Department of Pharmaceutical Microbiology of Warsaw Medical University of 1986 – 1990 a biologist, Research and Development Center of Biotechnology in Warsaw 4. Scientific achievement* according to the current regulations (article 16,paragraph 2 of the bill enacted on March 14, 2003, about scientific degrees and a scientific title as well as degrees and a title in arts (Dz. U. 2016 r. poz. 882 ze zm. w Dz. U. z 2016 r. poz. 1311.): a) the title of the scientific achievement : The structure, dissemination, and evolution of plasmids conferring antibiotic resistance b) Publications comprising scientific achievement: IF, impact factor is shown for the publication year The impact factor publications comprising scientific achievement: IF 19,073
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Izabela Kern-Zdanowicz Załącznik nr 3 Autoreferat w jęz. angielskim
1
SUMMARY OF PROFESSIONAL ACCOMPLISHMENTS
1. Name
Izabela Maria Kern-Zdanowicz
2. Education and obtained scientific titles
1997 – Doctor of Philosophy degree biochemistry
Institute of Biochemistry and Biophysics Polish Academy of Sciences
PhD thesis titled: „Secretion of streptokinase of Streptococcus equisimilis H46A in
bacterial homologous and heterologous systems, Supervisor: Piotr Cegłowski D. Sc.
Ph. D.
1986 – Master of Science title in biology/ specialization: molecular biology, Faculty of
Biology, University of Warsaw; Supervisor: prof. Ewa Bartnik
3. Employment in scientific institutions
2007 – till now employment as a research assistant in the Institute of Biochemistry
and Biophysics Polish Academy of Sciences in Warsaw,
1997 – 2007 employment as a research adjunct in the Institute of Biochemistry and
Biophysics Polish Academy of Sciences in Warsaw,
1992 – 1997 employment as a research assistant in the Institute of Biochemistry and
Biophysics Polish Academy of Sciences in Warsaw,
1990 – 1992 employment as a research assistant in Department of Pharmaceutical
Microbiology of Warsaw Medical University of
1986 – 1990 a biologist, Research and Development Center of Biotechnology in
Warsaw
4. Scientific achievement* according to the current regulations (article 16,paragraph 2 of the bill
enacted on March 14, 2003, about scientific degrees and a scientific title as well as degrees and a title in arts (Dz. U. 2016 r. poz. 882 ze zm. w Dz. U. z 2016 r. poz. 1311.):
a) the title of the scientific achievement :
The structure, dissemination, and evolution of plasmids conferring antibiotic resistance
b) Publications comprising scientific achievement: IF, impact factor is shown for the publication year The impact factor publications comprising scientific achievement: IF 19,073
Izabela Kern-Zdanowicz Załącznik nr 3 Autoreferat w jęz. angielskim
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1. Dmowski M., Gołębiewski M., Kern-Zdanowicz I.#. 2018. Characteristics of the conjugative transfer system of the IncM plasmid pCTX-M3 and identification of its putative regulators. J. Bacteriol. 200 (18): e00234-18, #
corresponding author
IF2016/2017 3,143
2. Wasyl D *, Kern-Zdanowicz I.*, Domańska-Blicharz K, Zając M, Hoszowski A. 2015. High-level fluoroquinolone resistant Salmonella enterica serovar Kentucky ST198 epidemic clone with IncA/C conjugative plasmid carrying blaCTX-M-25 gene. Vet Microbiol.;175(1):85-91. * joint first authorship
IF2015 2,564
3. Zienkiewicz M., Kern-Zdanowicz I., Carattoli A., Gniadkowski M., Cegłowski P. 2013.Tandem multiplication of the IS26-flanked amplicon with the blaSHV-5 gene within plasmid p1658/97. FEMS Microbiol Lett. 341:27-36. IF2013 2,723
4. Zienkiewicz M., Kern-Zdanowicz I., Gołębiewski M., Żylińska J., Mieczkowski P.,
Gniadkowski M., Bardowski J. and Cegłowski P. 2007. Mosaic structure of p1658/97, a 125-kilobase plasmid harbouring an active amplicon with the extended-spectrum β-lactamase gene blaSHV-5. Antimicrob Agents Chemother. 51:1164-1171. IF2007 4,39
5. Gołębiewski M., Kern-Zdanowicz I. #, Zienkiewicz M., Adamczyk M., Żylińska J., Baraniak A., Gniadkowski M., Bardowski J. and Cegłowski P.2007. Complete nucleotide sequence of the pCTX-M3 plasmid and its involvement in spread of the extended-spectrum β-lactamase (ESBL) gene blaCTX-M-3. Antimicrob Agents Chemother. 51: 3789-3795. #
corresponding author
IF2007 4,39
6. Nowakowska B., Kern-Zdanowicz I. #, Zielenkiewicz U. and Cegłowski P. 2005. Characterization of Bacillus subtilis clones surviving overproduction of Zeta, a pSM19035 plasmid-encoded toxin. Acta Biochim Polon., 52: 99–107. #
corresponding author
IF2005 1,862
b) Discussion of the scientific goals of the publications comprising the scientific achievement and potential of its further use
The papers included in the achievement are indicated in bold, those which I was a co-author and are cited only, are indicated with bolded numbers. .
Infections caused by strains of bacteria which are resistant to antibacterials, is now a
major problem of contemporary medicine. Increasing resistance to various groups of
therapeutics and the dissemination of the resistance in bacterial populations pushed the
World Health Organization (WHO) to establish the global priority list of antibiotic-resistant
Izabela Kern-Zdanowicz Załącznik nr 3 Autoreferat w jęz. angielskim
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bacteria. This list helps to guide research, discovery, and development of new antibiotics and
also the improvement of already existing drugs (1). The surveillance of bacteria resistant to
antibiotics originated from infections associated with health care and with animal husbandry
is systematically on-going. Also, the use of antibiotics is monitored. It is estimated that if a
fundamental change in the discovery of new antibiotics or in the development of an
alternative antibacterial therapy is not made by 2050, ten million lives a year can be lost due
to the infections of practically incurable infections caused by drug-resistant bacteria (2). To
the group of the highest priority, which is the group of the critically important pathogens,
are included: carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa,
as well as carbapenem-resistant or 3rd generation cephalosporin-resistant bacteria of the
Enterobacteriaceae family.
This study includes a set of six papers. Their main aim was the characterization of the
plasmids isolated from the bacterial strains which originated from hospital infections. Three
of the four plasmids analyzed (p1658/97, pCTX-M3 and p1643_10) confer resistance to 3rd
generation cephalosporin. These were isolated from representatives of the
Enterobacteriaceae family and classified as critically important pathogens according to the
WHO priority list. The research conducted on the fourth plasmid, pSM19035, chronologically
the earliest isolated one, was concentrated on selected aspects of its biology which could be
used in the search for new antibacterial therapies.
Plasmids, extrachromosomal DNA molecules, able to autonomously replicate are
important elements of the mobile gene pool, they enable bacteria the quick variability and
adaptability to the changing environment. Evolution of bacterial strains is constantly on-
going but selection of these which are resistant to antibiotics results in acceleration of
bacterial evolution. Plasmids are common in genomes of bacteria and archea (3, 4), where
they can constitute even up to 45% of genomic DNA (5). They are also found in eukaryotic
cells – in mitochondria and cytoplasm of fungi and in mitochondria of plants (6, 7). Plasmids
participate in horizontal gene transfer (HGT) – one of its mechanisms is a conjugative
plasmid transfer. One of the consequences of the latter is a dissemination of
chemotherapeutic resistance genes in the bacterial population. Of main importance are
conjugative plasmids which reside in cells of bacteria living in hospital environments or on
animal farms, i.e. wherever selective pressure in the form of antibiotics is used more
frequently and strongly than in other ecological niches. From such environments, large
plasmids bearing genes conferring resistance to many antibacterials are usually isolated and
these are the environments where the spread of antibiotic-resistant bacteria resistance is
monitored (8, 9).
Majority of plasmids exists in bacterial cells as covalently closed circles; however,
linear plasmids are also known (10). Plasmids significantly differ in size – there are small,
cryptic plasmids that comprise only a region responsible for plasmid replication, a replicon,
and also large plasmids, 100 – 200 kb in size. The largest are megaplasmids present in
Streptomyces - up to 1,8 Mb in size (11). Plasmid replication is precisely regulated in the host
cell and the copy number in which the plasmid exists in the host cell and the range of hosts
Izabela Kern-Zdanowicz Załącznik nr 3 Autoreferat w jęz. angielskim
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where the plasmid can replicate are fundamental characteristics for each plasmid. The
general rule is that small plasmids are present in a host cell in a high copy number and large
plasmids have a low number of copies (< 10). The plasmid can have a narrow host range
when its hosts are closely related bacteria or a broad host range when it can replicate in
phylogenetically distant bacteria (12, 13). Plasmids with the same replicon cannot stably co-
exist in a cell in the absence of external selection. One cell may contain a few plasmids if
they bear different replicons i.e. belong to different incompatibility groups (Inc).
Large plasmids are present in the cell in a low number of copies; however, they are
stably inherited in bacterial population due to encoded maintenance systems (14, 15). The
simplest, site-specific recombination system resolves plasmid oligomers, raised during
replication, into monomers, thus increasing the number of plasmid units to be segregated
into dividing cells. The second is a partition system, which leads to a physical movement of
plasmid copies to the cell regions which will the centers of the daughter cells after the cell
division (16). The third system, the addiction system, addicts the plasmid host cell from the
plasmid. In its classical form it comprises the stable toxin and the labile antidote, both
plasmid encoded (17). The loss of the plasmid results in the lack of de novo synthesis of
plasmid encoded proteins. The antidote still present in the cytoplasm of a bacterium is
degraded, this results in the release of the toxin from the complex in which it was inactive or
enables synthesis of the toxin. The toxin interacts with the cellular target, which leads to cell
death and the elimination of the plasmid-free cells from the population.
The fourth accessory system which confers stability of the plasmid in bacterial
population is a conjugative transfer system. This system recognizes each plasmid-free cell as
a potential recipient of the plasmid. This system is even more important – it is responsible
for the spread of the plasmids among bacteria. The majority of large plasmids present in
bacteria are conjugative ones. Only in Actinobacteria the dsDNA is transported in
conjugation from the donor to the recipient and the single protein participates in the
transfer (18). In other bacteria, and in archea, DNA is transported as a single strand, in a
complex with proteins. The transporter is constituted of the large protein complex, Mpf
(mating pair formation), responsible for formation of mating pair between the donor and
recipient. The Mpf complex is evolutionary related to the type IV protein secretion system
(T4SS), which is involved in the transport of proteins important in the virulence of some
pathogenic gram-negative bacteria into eukaryotic cells (19). DNA processing, necessary for
transfer, involves the nicking of one strand of the plasmid DNA at the specific nic site within
the origin of transfer (oriT) by relaxase. This enzyme remains covalently bound to the 5’ end
of DNA and together they are transferred to the recipient cell. The action of relaxase and the
Mpf complex are connected by the coupling protein (CP) (20).
Among T4SS, including plasmid Mpf systems, two phylogenetic groups, IVA and IVB,
can be distinguished. The first group, IVA, includes, for example, the conjugation system of
the F plasmid of the IncF group, which shows evolutionary similarities to the IVA prototype,
namely, the oncogenic T-DNA transfer system of Agrobacterium tumefaciens. However, the
second group, IVB, includes those which are homologous to Dot/Icm proteins constituting
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the transport system of proteins involved in a virulence of Legionella pneumophila, the
causative agent of the Legionnaires' disease. This group are includes the conjugation system
of the IncI1 group plasmids, such as R64 or ColIb-P9, and the conjugation system of pCTX-
M3, I am analyzing, which will be described below. T4BSS systems are less thoroughly
analyzed than T4ASS. Another classification of the Mpf systems of conjugative plasmids
distinguished eight MPF groups and it is based on phylogeny of the VirB4 protein, the only
protein homologues of which were found in all known conjugation systems (21).
To be transferred during conjugation, the plasmid must comprise the oriT sequence
as well as both complexes, the relaxase and Mpf, and also the coupling protein have to be
synthesized in the host cell. Conjugative plasmids code for all these elements. However,
there are also other mobilizable plasmids which can utilize Mpf or Mpf and CP of the
conjugative plasmid co-residing in one host cell, so the conjugative plasmid serves as a
helper plasmid to the mobilizable one. Plasmids which are mobilized to transfer may
comprise the oriT only if it is compatible with the conjugation system of the helper plasmid
present within the bacterial cell (22). Similarly, the structures present in genomes of
bacteria, such as genomic island or pathogenicity islands, can be mobilized when they
comprise the oriT region compatible with conjugative plasmids or ICEs (integrative
conjugative elements, formerly called conjugative transposons) co-existing in the cell (23,
24).
In the plasmid, genetic modules which encode the ability to replicate, to be stably
maintained in the bacterial population, and to be conjugatively transferred, constitute the
plasmid backbone which is conserved in evolution. The variable, accessory regions which are
acquired during the evolution of the plasmid are called a load (25). This load, even if it
causes the metabolic burden in the host cell, plays an important role in increasing the
adaptability of the host.
As a load, plasmids bear genes conferring resistance to major antibacterials such as