Протеїнкіназа PknB як перспективна мішень для розробки антибактеріальних препаратів проти Staphylococcus aureus
Antibiotic resistance is one of the biggest challenges in modern medicine. Uncontrolled use of antibiotics has led to the emergence of multidrug and extensively drug-resistant bacterial strains which are non-susceptible to almost all currently known antimicrobial drugs. Unfortunately, only a few nov...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
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| author | Moskovets, Anastasiia O. Pletnova, Larysa V. Maiula, Taras G. Tverdyy, Dmytro O. Volynets, Galyna P. |
| author_facet | Moskovets, Anastasiia O. Pletnova, Larysa V. Maiula, Taras G. Tverdyy, Dmytro O. Volynets, Galyna P. |
| author_institution_txt_mv | [
{
"author": "Anastasiia O. Moskovets",
"institution": "Taras Shevchenko National University of Kyiv, Kyiv, Ukraine"
},
{
"author": "Larysa V. Pletnova",
"institution": "Institute of Molecular Biology and Genetics of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Taras G. Maiula",
"institution": "Institute of Molecular Biology and Genetics of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Dmytro O. Tverdyy",
"institution": "Institute of Molecular Biology and Genetics of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Galyna P. Volynets",
"institution": "Institute of Molecular Biology and Genetics of the NAS of Ukraine, Kyiv, Ukraine; Scientific service company «OTAVA» LLC, Kyiv, Ukraine"
}
] |
| author_sort | Moskovets, Anastasiia O. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:54Z |
| description | Antibiotic resistance is one of the biggest challenges in modern medicine. Uncontrolled use of antibiotics has led to the emergence of multidrug and extensively drug-resistant bacterial strains which are non-susceptible to almost all currently known antimicrobial drugs. Unfortunately, only a few novel antibacterial drugs have been developed in recent decades. Approximately 30% of the human population is colonized by Staphylococcus aureus. Unfortunately, the treatment of staphylococcal infections is complicated due to the ability of S. aureus to produce antibiotic-neutralizing enzymes. Today, methicillin-(MRSA) and vancomycin-resistant (VRSA) S. aureus strains are very widespread in the world and become serious medical and public problem. For example, in 2019, more than 1 million people died from infections caused by antibiotic-resistant S. aureus. Therefore, the search of novel antistaphylococcal agents with unexploited mechanisms of action is of urgent need. The serine/threonine protein kinase PknB is involved in a number of important signaling pathways of S. aureus, such as cell wall metabolism, antibiotic susceptibility, and virulence regulation. Taking into account that protein kinase PknB is a key component of the bacterial cell signaling network involved in a number of important biological processes, this enzyme can be considered as a promising molecular target for the search of novel inhibitors as antibacterial agents [7]. In this review we analyzed the current data on the structure, mechanisms of PknB activity regulation and functions, and also summarized the results of inhibitors search. |
| doi_str_mv | 10.15407/bioorganica2023.01.003 |
| first_indexed | 2025-07-17T12:19:47Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
UDC 577.322
DOI: https://doi.org/10.15407/bioorganica2023.01.003
3
REVIEW
Protein kinase PknB as a promising target for the development of
antibacterial drugs toward Staphylococcus aureus
Anastasiia O. Moskovets1, Larysa V. Pletnova2, Taras G. Maiula2, Dmytro O. Tverdyy2,
Galyna P. Volynets2,3*
1 Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
2 Institute of Molecular Biology and Genetics of the NAS of Ukraine, Kyiv, Ukraine
3 Scientific service company «OTAVA» LLC, Kyiv, Ukraine
Abstract: Antimicrobial resistance is one of this century's most serious global public health threats. Uncontrolled use of antibiotics has led
to extensively drug-resistant bacterial strains which are non-susceptible to almost all currently known antimicrobial drugs. Staphylococcus
aureus is the pathogen of most significant concern in the clinic worldwide because it colonized approximately 30% of the human
population. Therefore, the search for new antistaphylococcal drugs is an urgent need of mankind. In prokaryotic cells, a number of cellular
processes are regulated by serine/threonine protein kinases. In particular, the protein kinase PknB is a key component of the signaling
network of bacterial cells, which can be considered as a promising molecular target for the search for new antibacterial drugs. In this
review we focus on the structure, functions and mechanisms of PknB activity regulation. We also summarized recent research results of its
inhibitors search.
Keywords: antimicrobial resistance; antibacterial drugs; Staphylococcus aureus; protein kinase PknB; inhibition.
Introduction
Antibiotic resistance is one of the biggest challenges in
modern medicine. Uncontrolled use of antibiotics has led to
the emergence of multidrug and extensively drug-resistant
bacterial strains which are non-susceptible to almost all
currently known antimicrobial drugs. Unfortunately, only a
few novel antibacterial drugs have been developed in recent
decades.
Approximately 30% of the human population is
colonized by Staphylococcus aureus [1]. S. aureus is an
opportunistic pathogen which is normally found on the skin
and mucous membranes of the upper respiratory tract.
S. aureus is a causative pathogen for a number of human
diseases ranging from minor skin infections to
Received:
Revised:
Accepted:
Published online:
05.05.2023
15.05.2023
30.05.2023
30.06.2023
Corresponding author. Tel.: +380-68-635-4530;
e-mail: g.p.volynets@gmail.com (G.P. Volynets)
ORCID: 0000-0002-0166-2642
life-threatening bacteremia, sepsis, and meningitis [2].
Unfortunately, the treatment of staphylococcal infections is
complicated due to the ability of S. aureus to produce
antibiotic-neutralizing enzymes [3]. Today, methicillin-
(MRSA) and vancomycin-resistant (VRSA) S. aureus
strains are very widespread in the world and become serious
medical and public problem. For example, in 2019, more
than 1 million people died from infections caused by
antibiotic-resistant S. aureus [5]. Therefore, the search of
novel antistaphylococcal agents with unexploited mecha-
nisms of action is of urgent need.
The serine/threonine protein kinase PknB is involved in a
number of important signaling pathways of S. aureus, such
as cell wall metabolism, antibiotic susceptibility, and
virulence regulation [6]. Taking into account that protein
kinase PknB is a key component of the bacterial cell
signaling network involved in a number of important
biological processes, this enzyme can be considered as a
promising molecular target for the search of novel inhibitors
as antibacterial agents [7]. In this review we analyzed the
current data on the structure, mechanisms of PknB activity
regulation and functions, and also summarized the results of
inhibitors search.
© Moskovets A.O. 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.
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
https://orcid.org/0000-0002-0166-2642
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
4
Structure of S. aureus PknB
Protein phosphorylation is one of the key regulatory
mechanisms in bacteria that controls major metabolic
pathways, cell wall biosynthesis, production of various
toxins, expression of virulence factors, biofilm formation,
antibiotic resistance, etc. Usually, extracellular signals are
transformed into cellular responses by regulating the
activity of the corresponding proteins depending on the
phosphorylation of specific amino acid residues sites
containing serine, threonine or tyrosine [8].
S. aureus encodes an eukaryotic-type serine/threonine
protein kinase, PknB (Stk1), which plays an important role
in cell wall metabolism, virulence, and drug resistance.
Depending on the presence of arginine amino acid residue,
which precedes the conserved catalytic aspartic acid,
serine/threonine protein kinases can be classified into RD
and non-RD kinases. PknB belongs to RD family kinase
and contains N-terminal intracellular kinase domain,
hydrophobic transmembrane domain, three extracellular
PASTA domains (for penicillin-binding protein and
serine/threonine kinase-associated domains) and an Ig-like
domain at the C-terminus. PASTA domains consist of ∼65
amino acids and are considered to be sensory motives for
the binding of β-lactam compounds as well as cell wall
fragments (e.g., peptidoglycans) [9]. PknB is of particular
importance for the survival and pathogenesis of S. aureus,
since this protein kinase regulates purine biosynthesis,
autolysis, and other central metabolic processes of the
bacterium and is involved in the development of antibiotic
resistance [7].
Interestingly, deletion of pknb leads to β-lactam
antibiotics susceptibility of MRSA, indicating that PknB
may be a potential target for combination therapy [10, 11].
Regulation of PknB activity in S. aureus
The regulation of cellular processes by the protein kinase
PknB and its corresponding phosphatase Stp is widespread
in bacteria, in particular in S. aureus [12].
The protein kinase PknB possesses six physiological
phosphorylation sites (Ser159, Thr161, Ser162, Thr164,
Thr166, and Thr172) which are required for the regulation
of catalytic activity. This means that differential
phosphorylation of the activation loop regulates the kinase
activity of PknB. Interestingly, it was found that the
replacement of Thr172 in the GT/S motif with Ala or Asp
leads to the formation of non-functional form of this protein
kinase, indicating that the phosphorylation of Thr172 is
crucial for PknB activation. The protein kinase PknB uses a
cis-autophosphorylation mechanism to transfer phosphate
from ATP to Thr172. Other serines/threonines located in
the activation loop are phosphorylated by the trans-
autophosphorylation mechanism. If Thr172 is not
phosphorylated, phosphorylation of other residues in the
activation loop does not affect the kinase activity of PknB,
which confirms that phosphorylation of Thr172 is the first
step for PknB activation [9].
A model of activation of the protein kinase PknB was
proposed. In the inactive state, the unphosphorylated
activation loop is folded into the catalytic cleft, mimicking a
substrate, which prevents substrate binding. Under external
stimulation, ATP binding triggers cis-autophosphorylation
of Thr172, changing the conformation of the activation
loop, which leads to PknB activation. Subsequent
interaction with other PknB molecule induces trans-
autophosphorylation of other residues in the activation loop
to support optimal kinase activity. The mutation of Thr172
results in a complete loss of kinase activity, regardless of
the phosphorylation state of other residues in the activation
loop. The related phosphatase Stp dephosphorylates protein
kinase PknB, restoring the inactive, unphosphorylated
kinase [9].
Therefore, the phosphorylation of Thr172 of the GT/S
motif in the activation loop is necessary for S. aureus PknB
activation.
Taking into account high sequence variability in the
activation loop of bacterial serine/threonine protein kinases,
the understanding of PknB autophosphorylation
mechanisms has practical implications for the rational
design of selective and effective PknB inhibitors to combat
antibiotic-resistant S. aureus [9].
Involvement of PknB in the formation of S. aureus
virulence
Bacteria adapt to different environments to survive in
changing conditions, and, accordingly, they have a number
of protein kinases involved in signal recognition and
transduction [13]. The most known signaling cascades in
bacteria are two-component systems, which generally
consist of a membrane histidine kinase that senses an
extracellular signal, autophosphorylates histidine residue,
and transfers the phosphate group to an aspartate residue of
downstream regulator or transcription factor [14].
Serine/threonine phosphorylation, which is the main
mechanism of cellular function regulation in eukaryotes,
was identified in bacteria much later and quickly became an
object of great interest due to its involvement in virulence
[15]. Serine/threonine kinases were described in a number
of bacteria and regulate a wide range of bacterial functions,
including glycolysis, protein translation, sporulation, and in
pathogenic bacteria, virulence and antibiotic resistance [16].
The serine/threonine protein kinase PknB and
phosphatase Stp were characterized in S. aureus, a
bacterium which adapts well to different conditions and
quickly develops resistance to many antibiotics. Deletion
and overexpression strains of PknB and Stp were used to
study the functions of corresponding enzymes in
experiments in vitro and in vivo [11].
A recent study has demonstrated that serine/threonine
phosphorylation is involved in S. aureus metabolism
regulation which allows bacteria grow on different
substrates. A detailed metabolic model of this metabolic
adaptation was constructed and quantitatively validated
with an independent experimental transcriptomic dataset
A.O. Moskovets, L.V. Pletnova et al.
5
from S. aureus strain. According to this hypothesis PknB
and its close association with the glmR regulator and the
cdaA operon supports a stable glucose flux, improved
synthesis of aromatic amino acids, nucleotides and
peptidoglycan. Also, PknB is important for cell wall
homeostasis by activating central virulence regulators
(AgrABCD, ArlS, SaeRS, SarA, and MgrA), which affects
virulence and antibiotic resistance [7].
Therefore, taking into account the role of PknB in
virulence, this protein kinase can be considered as a
potential therapeutic target for the treatment of S. aureus
infections.
Role of PknB in the regulation of S. aureus growth
and antibiotic resistance
Despite the fact that S. aureus is a usual member of the
microbiota in healthy persons, it can cause a wide range of
diseases. In addition to skin infections, S. aureus causes
life-threatening invasive disorders such as bacteremia,
endocarditis, and osteomyelitis [17]. The development of
bacterial resistance to a number of antibiotics, such as
penicillin, methicillin, and vancomycin, makes these
infections quite difficult to treat [18]. Most antibiotics are
effective toward metabolically active bacteria. Thus,
bacteria with reduced energy consumption, which leads to
metabolic dormancy, have increased resistance to
antibiotics [11].
Signal transduction through protein phosphorylation is
the main regulatory mechanism that provides the rapid
response to environmental changes [19]. In S. aureus, a
eukaryotic-type serine/threonine kinase PknB and related
phosphatase Stp can regulate basic cellular processes,
allowing bacteria to quickly respond to environmental
changes and regulate the dormancy [22].
Recent studies have shown that the serine/threonine
kinase PknB and phosphatase Stp regulate antibiotic
resistance in S. aureus persistent strains. Recently, the
authors Huemer et al. found that conditions mimicking acid
stress experienced by S. aureus in host tissues significantly
changed the serine and threonine phosphoproteome, and
increased threonine phosphorylation in the activation loop
of PknB. It was shown that the deletion of stp increases the
subpopulation of dormant bacteria in response to stress.
Additional analyses demonstrated that the Δstp mutant has
lower levels of intracellular ATP, reduced protein
translation and increased antibiotic tolerance. Using
phosphoproteomic approaches authors identified the targets
of Ser/Thr phosporylation regulating bacterial growth and
metabolism such as ribosomal proteins including elongation
factor EF-G [12]. It may be concluded that the process of
serine/threonine phosphorylation regulates bacterial
quiescence and antibiotic tolerance despite full
susceptibility of S. aureus to antibiotics. Therefore,
inhibition of PknB and Stp can be promising therapeutic
strategy to prevent S. aureus persister formation.
Involvement of PknB in S. aureus cell wall
synthesis
The search for new antibiotics targeting the pathways of
cell wall biosynthesis is the most promising strategy to
combat antibiotic resistance [23].
The bacterial cell envelope is essential for bacterial
survival under environmental stresses and contributes to
virulence and antibiotic resistance. The cell wall of Gram-
positive bacteria consists of a multilayered network of
cross-linked peptidoglycan (PGN). PGN is composed
of repeating disaccharide chains including
N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid
(MurNAc). The lactoyl group of MurNAc is substituted by
a peptide stem (L-Ala-D-isoGlu-L-Lys-D-Ala-D-Ala). The
polysaccharide chains of staphylococcal PGN are strongly
cross-linked by interpeptide bridges of five glycyl residues
protruding from the L-lysine of the stem peptides. The
overall synthesis of PGNs can be divided into three main
steps: (1) formation of a nucleotide sugar-linked precursor
UDP-MurNAc pentapeptide (Park's nucleotide), (2) transfer
of the soluble PGN precursor to the lipid carrier
undecaprenyl diphosphate (formation of lipid I) and
attachment of UDP-GlcNAc, resulting in the formation of
lipid II, and (3) transport of this subunit across the
cytoplasmic membrane and cross-bridge formation [24].
Several studies have shown that phosphorylation plays
an important role in cell wall metabolism [25, 26].
Particularly, it was shown that the serine/threonine protein
kinase PknB and the related phosphatase Stp in S. aureus
are involved in the signaling during cell wall synthesis. It
was found that pentaglycine-lipid II interacts with
extracellular PASTA domains of the PknB which in turn
leads to the activation of protein kinase activity [22].
Indeed, the deletion of pknb and stp causes cell division
defects in S. aureus, leading to the formation of multiple
and incomplete septa, changes in cell size and cell wall
thickness [6]. In addition, pknb and pknb/stp deletion strains
are more sensitive to antibiotics that act through the cell
wall, such as tunicamycin and fosfomycin [27]. In addition,
Stp phosphatase contributes to vancomycin sensitivity and
virulence [28]. PknB cross-talks with two-component
systems are implicated in cell wall metabolism by
phosphorylating the response regulators VraTSR8,
WalRK9, and GraSR24, affecting the expression of cell
wall stimulators and hydrolases, as well as cell wall charge
[29, 30]. PknB homologs also regulate cell wall synthesis
and cell division in Streptococcus, Bacillus, and
Streptomyces [31-33].
In many Gram-positive bacteria, including S. aureus, the
transpeptidase enzyme sortase A (SrtA) attaches surface
proteins to the cell wall and plays an important role in
bacterial pathogenesis. In S. aureus, SrtA is phosphorylated
by PknB and by the low molecular weight phosphodonor
acetyl phosphate (AcP) in vitro. Both PknB- and AcP-
mediated phosphorylation inhibit the enzymatic activity of
SrtA in vitro. Also, it was demonstrated that the deletion of
the stp gene encoding the serine/threonine phosphatase Stp
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
6
resulted in an increase in the level of SrtA phosphorylation
[34].
Based on these findings, PknB and/or Stp inhibitors can
be promising antibacterial agents for the treatment of S.
aureus infections.
S. aureus PknB inhibitors
Arylsulfonamides as adjuvants of bactericidal activity of
β-lactams.
β-Lactams are widely used to treat infections caused by
Staphylococcus aureus. But, modification and expression of
penicillin-binding proteins (PBPs), drug inactivation by
synthesis of β-lactamases, decreasing drug effectiveness due
to biofilm formation, and expression of an efflux pumps all
caused the development of S. aureus resistance to β-lactam
antibiotics. The synthesis of β-lactamases and modification
of PBPs led to penicillin resistance. With the emergence of
MRSA strains, the resistance to methicillin was also
reported. Then MRSA infections were treated with
cephalosporin and carbapenems, but resistant strains have
also emerged during these antibiotic therapies.
S. aureus is one of the priority resistant pathogen
microorganisms that require the development of novel
antibiotics and innovative preventive approaches [35].
There is a growing interest in the use of adjuvants to
restore MRSA susceptibility to β-lactams. Adjuvants are
auxiliary compounds for antibiotics that enhance their
effect, for example, by inhibiting bacterial resistance
mechanisms [36].
The use of eukaryotic serine/threonine kinase inhibitors
demonstrates potent antibiotic efficacy against various types
of bacteria, including MRSA, enterococci, mycobacteria,
and gram-negative bacteria. Previously, it was reported that
inhibitors targeting bacterial protein kinases enhance the
antibacterial activity of β-lactam antibiotics [7]. Inhibiting
PknB with small molecule inhibitors improves the efficacy
of β-lactam antibiotics such as nafcillin and imipenem.
Genetic deletion of PknB increases the susceptibility of S.
aureus to β-lactams. However, no changes were found in
the sensitivity to vancomycin.
The screening of a small library of drugs for inhibitory
activity toward PknB revealed four arylsulfonamides that
were active at a concentration of 2 μM. The general
chemical structure of arylsulfonamides is presented in
Figure 1. Staurosporine, a pan-kinase inhibitor, was also
active. These inhibitors are adjuvants of the bactericidal
activity of β-lactam antibiotics and can inhibit bacterial
growth by 50% at a concentration of 13 μM. None of the
four sulfonamides were toxic in animal models. In an in
vitro growth assay, none of the MRSA strains were
inhibited by the presence of 4 mg/L-1 nafcillin. On the
contrary, at the same concentration of nafcillin and in the
presence of 13 μM sulfonamide (or staurosporine), bacterial
growth was inhibited by 50%. Thus, PknB inhibitors are
adjuvants of the bactericidal activity of β-lactams [37].
Figure 1. Chemical structure of arylsulfonamides.
Pyrazolo[3,4-d]pyrimidines
A recent study revealed the powerful antibacterial
potential of pyrazolo[3,4-d]pyrimidines, which are
promising protein kinase inhibitors possessing
antiproliferative properties [38]. In particular, six
compounds were identified that showed bacteriostatic
activity against gram-positive S. aureus and gram-negative
E. coli [39]. The pyrazolo[3,4-d]pyrimidine compounds 1-6,
presented in Figure 2, were tested for their antibacterial
activity against S. aureus and E. coli. These studies showed
that all investigated compounds have significant
antibacterial activity against S. aureus and E. coli.
Compound 3 at a concentration of 200 μg/mL was able to
almost completely inhibit the growth of S. aureus.
Compounds 1 and 4 did not show growth inhibition alone at
12.5 μg/mL or 25 μg/mL, but in combination with sublethal
doses of ampicillin (0.02 μg/mL), a significant bacterial
growth inhibition was observed within 14 hours. Compound
4 showed a moderate increase of kanamycin activity
(0.2 μg/mL) in S. aureus [12, 39].
Triarylimidazole derivatives
Triarylimidazole derivatives inhibit S. aureus PknB and
enhance activity of β-lactam antibiotics. For example, it was
established that compound 7 (Figure 2) at a concentration of
7 mg/L-1 decreased the MIC value of oxacillin from
256 mg/L-1 to 4 mg/L-1 for MRSA252 strain; from
16 mg/L-1 to 4 mg/L-1 for MRSA NRS123 strain; and from
32 mg/L-1 to 0.5 mg/L-1 for MRSA NRS70 strain [37].
GW779439X and its pyrazolopyridazine derivatives
The compound GW779439X (compound 8, Figure 2)
was identified as a novel inhibitor of S. aureus PknB. The
inhibitor GW779439X enhanced the effect of β-lactams, in
particular, MRSA-active ceftaroline, against several MSSA
and MRSA strains. GW779439X at the concentration of
5 μM reduced the MIC of ceftaroline by 2-fold for MRSA
USA 300-LAC strain. After addition of GW779439X 2-fold
decrease was also observed for meropenem, 8-fold for
nafcillin, and 16-fold for oxacillin, while the MIC for
vancomycin did not change [37].
Seven derivatives of GW779439X were synthesized and
structure-activity relationships were studied. It was found
that the presence and orientation of the methylpiperazine is
important for inhibitory activity toward S. aureus PknB
(Figure 3). Particularly, the presence of a positive charge on
p-N-methylpiperazine is crucial for inhibitory activity [40].
Therefore, pyrazolopyridazine scaffold is promising for the
development of S. aureus PknB inhibitors as antibiotic
adjuvants.
A.O. Moskovets, L.V. Pletnova et al.
7
Figure 2. Chemical structure of PknB inhibitors: pyrazolo[3,4-d]pyrimidine derivatives (1-6), 4-[5-(4-Fluoro-phenyl)-2-(4-isobuthyl-
phenyl)-1H-imidazol-4-yl]-pyridine (7), GW779439X (8), loratadine (9), Inh2-B1 (10).
N
NN
N
N
N
H
N
N
CAF 045
N
NN
N
N
N
H
N
N
F
CAF 052
N
NN
N
N
N
H CF3
CAF 070
N
N
NN
N
N
N
H
OMe
CAF 075
N
NN
N
N
N
H N
CAF 077
N
NN
N
N
N
H
N
CAF 078
N
N
N
H CF3
H
N
NN
N
N
N
H
N
CH3
CAF 089
N
Figure 3. Structures of pyrazolopyridazine compounds.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
8
Loratadine
The non-toxic antihistamine loratadine (compound 9,
Figure 2) was identified as an inhibitor of S. aureus PknB,
which inhibits biofilm formation and enhances the activity
of β-lactam antibiotics and vancomycin. During comparison
of the activity of loratadine with a structurally similar
compound, desloratadine, was revealed that the presence of
ethyl carboxyester in the structure of loratadine is crucial
for PknB inhibitory activity and consequently for
antibacterial activity in both biofilm inhibition assay and the
antibiotic potency assay, since desloratadine was not active
[41].
Quinazoline-based inhibitors.
The small molecule compound methyl 5-oxo-3-
(phenylcarbamoyl)-1-thioxo-4,5-dihydro[1,3]thiazolo[3,4-
a]quinazoline-8-carboxylate (Inh2-B1) was identified as
ATP-competitive PknB inhibitor. Although Inh2-B1
(compound 10, Figure 2) is a relatively weak inhibitor
(IC50 = 50 μM) of PknB autophosphorylation, it, in
combination with β-lactam, protected mice from the lethal
effects of MRSA. Separately, β-lactam and Inh2-B1 were
ineffective. However, only Inh2-B1 inhibited biofilm
formation [37].
The quinazoline core is typical for many eukaryotic
kinase inhibitors. Several aminoquinazoline-based
inhibitors (mitoxantrone, VI12112) have been previously
described as inhibitors of the mycobacterial PknB.
Quinazoline inhibitor AX20017 blocks the activity of
PknG, a PASTA-free mycobacterial kinase that promotes
bacterial survival inside human macrophages. AX20017
restores macrophage-mediated killing but does not inhibit
the growth of extracellular bacteria [42].
The compound Inh2-B1 acts as so-called antibiotic
resistance breaker by inhibiting the kinase activity of S.
aureus PknB, which contributes significantly to antibiotic
resistance by modulating the function of cell wall
biosynthesis mechanisms. In high concentrations, neither
Inh2-B1, nor ceftriaxone, or cefotaxime can inhibit bacterial
growth by themselves. Therefore, Inh2-B1 is effective when
used in combination therapy with low-efficient
cephalosporins [12].
Inh2-B1 is not cytotoxic and does not have apoptotic
effects on human cells. The last property is very important,
since a lot of protein kinase inhibitors are successfully used
to treat tumors due to their ability to induce apoptosis in
human cells. Inh2-B1 downregulates cell wall hydrolase
genes and disrupt MRSA biofilm formation which makes
this inhibitor a therapeutically important agent to overcome
antibiotic resistance [6].
Therefore, serine/threonine protein kinase PknB is a
valuable molecular target for the development of novel
antibacterial compounds toward Staphylococcus aureus.
Several classes of inhibitors have been already reported, but
none of them demonstrate high activity. Therefore, the
search of novel classes and optimization of known PknB
inhibitors is of great interest.
Notes
The authors declare no conflict of interest.
Author contributions. The manuscript was written
through contributions of all authors. All authors have given
approval to the final version of the manuscript.
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Протеїнкіназа PknB як перспективна мішень для розробки антибактеріальних
препаратів проти Staphylococcus aureus
А.О. Московець1, Л.В. Плетньова2, Т.Г. Маюла2, Д.О. Твердий2, Г.П.. Волинець2,3*
1 Київський національний університет імені Тараса Шевченка, Київ, Україна
2 Інститут молекулярної біології і генетики НАН України, Київ, Україна
3 Наукова установа ТОВ «Науково-сервісна фірма ˝ОТАВА »̋, м. Київ
Резюме: Резистентність до протимікробних препаратів є однією з найсерйозніших глобальних загроз громадському здоров’ю нашого століття.
Неконтрольоване застосування антибіотиків призвело до широкого розповсюдження штамів бактерій, які несприйнятливі майже до вс іх відомих
на сьогодні антимікробних препаратів. Одним з патогенів, що викликає найбільше занепокоєння в клінічній практиці, є Staphylococcus aureus,
оскільки він колонізував приблизно 30% людської популяції. Тому пошук нових протистафілококових препаратів є невідкладною потребою
людства. У прокаріотичних клітинах низка клітинних процесів регулюється серин/треоніновими протеїнкіназами. Зокрема, протеїнкіназа PknB є
ключовим компонентом сигнальної мережі бактеріальних клітин, що дає змогу розглядати цей фермент як перспективну молекулярну мішень для
пошуку нових антибактеріальних препаратів. У цьому огляді ми проаналізували сучасні дані щодо структури та механізму регуляції
протеїнкінази PknB, а також результати досліджень стосовно пошуку її інгібіторів.
Ключові слова: протимікробна стійкість; антибактеріальні препарати; золотистий стафілокок Staphylococcus aureus; протеїнкіназа PknB;
інгібування.
|
| id | oai:ojs2.bioorganica.com.ua:article-47 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:04Z |
| publishDate | 2023 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/a3/59c3e3c6fa395df6b9f662ba8dd6d9a3.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-472026-07-19T14:56:54Z Protein kinase PknB as a promising target for the development of antibacterial drugs toward Staphylococcus aureus Протеїнкіназа PknB як перспективна мішень для розробки антибактеріальних препаратів проти Staphylococcus aureus Moskovets, Anastasiia O. Pletnova, Larysa V. Maiula, Taras G. Tverdyy, Dmytro O. Volynets, Galyna P. Antibiotic resistance antibacterial drugs Staphylococcus aureus Антибіотикорезистентність антибактеріальні препарати Staphylococcus aureus Antibiotic resistance is one of the biggest challenges in modern medicine. Uncontrolled use of antibiotics has led to the emergence of multidrug and extensively drug-resistant bacterial strains which are non-susceptible to almost all currently known antimicrobial drugs. Unfortunately, only a few novel antibacterial drugs have been developed in recent decades. Approximately 30% of the human population is colonized by Staphylococcus aureus. Unfortunately, the treatment of staphylococcal infections is complicated due to the ability of S. aureus to produce antibiotic-neutralizing enzymes. Today, methicillin-(MRSA) and vancomycin-resistant (VRSA) S. aureus strains are very widespread in the world and become serious medical and public problem. For example, in 2019, more than 1 million people died from infections caused by antibiotic-resistant S. aureus. Therefore, the search of novel antistaphylococcal agents with unexploited mechanisms of action is of urgent need. The serine/threonine protein kinase PknB is involved in a number of important signaling pathways of S. aureus, such as cell wall metabolism, antibiotic susceptibility, and virulence regulation. Taking into account that protein kinase PknB is a key component of the bacterial cell signaling network involved in a number of important biological processes, this enzyme can be considered as a promising molecular target for the search of novel inhibitors as antibacterial agents [7]. In this review we analyzed the current data on the structure, mechanisms of PknB activity regulation and functions, and also summarized the results of inhibitors search. Стійкість до антибіотиків є однією з найбільших проблем сучасної медицини. Неконтрольоване застосування антибіотиків призвело до появи штамів бактерій, які мають широку лікарську стійкість, які не сприйнятливі майже до всіх відомих на сьогодні антимікробних препаратів. На жаль, за останні десятиліття було розроблено лише кілька нових антибактеріальних препаратів. Приблизно 30% людської популяції колонізовано Staphylococcus aureus. На жаль, лікування стафілококових інфекцій ускладнене через здатність S. aureus виробляти антибіотиконейтралізуючі ферменти. Сьогодні метицилін-(MRSA) і ванкоміцин-резистентні (VRSA) штами S. aureus дуже поширені у світі і становлять серйозну медичну та громадську проблему. Наприклад, у 2019 році понад 1 мільйон людей померли від інфекцій, спричинених стійким до антибіотиків S. aureus. Тому пошук нових протистафілококових препаратів з невикористаними механізмами дії є гострою потребою. Протеїнкіназа серин/треонін PknB бере участь у ряді важливих сигнальних шляхів S. aureus, таких як метаболізм клітинної стінки, чутливість до антибіотиків і регуляція вірулентності. Враховуючи, що протеїнкіназа PknB є ключовим компонентом сигнальної мережі бактеріальної клітини, яка бере участь у ряді важливих біологічних процесів, цей фермент можна розглядати як перспективну молекулярну мішень для пошуку нових інгібіторів як антибактеріальних засобів [7]. В огляді проаналізовано сучасні дані щодо структури, механізмів регуляції активності та функцій PknB, а також узагальнено результати пошуку інгібіторів. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2023-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/47 10.15407/bioorganica2023.01.003 Ukrainica Bioorganica Acta; Vol. 18 No. 1 (2023): Ukrainica Bioorganica Acta; 3-9 Ukrainica Bioorganica Acta; Том 18 № 1 (2023): Ukrainica Bioorganica Acta; 3-9 1814-9766 1814-9758 10.15407/bioorganica2023.01 en https://bioorganica.com.ua/index.php/journal/article/view/47/56 Copyright (c) 2023 Anastasiia O. Moskovets, Larysa V. Pletnova, Taras G. Maiula, Dmytro O. Tverdyy, Galyna P. Volynets https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | Антибіотикорезистентність антибактеріальні препарати Staphylococcus aureus Moskovets, Anastasiia O. Pletnova, Larysa V. Maiula, Taras G. Tverdyy, Dmytro O. Volynets, Galyna P. Протеїнкіназа PknB як перспективна мішень для розробки антибактеріальних препаратів проти Staphylococcus aureus |
| title | Протеїнкіназа PknB як перспективна мішень для розробки антибактеріальних препаратів проти Staphylococcus aureus |
| title_alt | Protein kinase PknB as a promising target for the development of antibacterial drugs toward Staphylococcus aureus |
| title_full | Протеїнкіназа PknB як перспективна мішень для розробки антибактеріальних препаратів проти Staphylococcus aureus |
| title_fullStr | Протеїнкіназа PknB як перспективна мішень для розробки антибактеріальних препаратів проти Staphylococcus aureus |
| title_full_unstemmed | Протеїнкіназа PknB як перспективна мішень для розробки антибактеріальних препаратів проти Staphylococcus aureus |
| title_short | Протеїнкіназа PknB як перспективна мішень для розробки антибактеріальних препаратів проти Staphylococcus aureus |
| title_sort | протеїнкіназа pknb як перспективна мішень для розробки антибактеріальних препаратів проти staphylococcus aureus |
| topic | Антибіотикорезистентність антибактеріальні препарати Staphylococcus aureus |
| topic_facet | Antibiotic resistance antibacterial drugs Staphylococcus aureus Антибіотикорезистентність антибактеріальні препарати Staphylococcus aureus |
| url | https://bioorganica.com.ua/index.php/journal/article/view/47 |
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