Beta-lactamase

Beta-lactamases are enzymes (EC 3.5.2.6) produced by bacteria that

Beta-lactamase
provide multi-resistance to β-lactam antibiotics such as penicillins,
cephalosporins, cephamycins, and carbapenems (ertapenem), although
carbapenems are relatively resistant to beta-lactamase. Beta-lactamase
provides antibiotic resistance by breaking the antibiotics' structure.
These antibiotics all have a common element in their molecular
structure: a four-atom ring known as a β-lactam. Through hydrolysis,
the lactamase enzyme breaks the β-lactam ring open, deactivating the
molecule's antibacterial properties.

Beta-lactam antibiotics are typically used to treat a broad spectrum of

Gram-positive and Gram-negative bacteria.

Beta-lactamases produced by Gram-negative organisms are usually Structure of a Streptomyces albus beta-
[1]
secreted, especially when antibiotics are present in the environment. lactamase
Identifiers
Symbol β-lactamase domain
Contents Pfam PF00144
Structure Pfam clan CL0013
Penicillinase
InterPro IPR001466
Resistance in Gram-negative bacteria
Extended-spectrum beta-lactamase (ESBL)
PROSITE PS00146
Types SCOP 56601
TEM beta-lactamases (class A)
SUPERFAMILY 56601
SHV beta-lactamases (class A)
CTX-M beta-lactamases (class A) Available protein structures:
OXA beta-lactamases (class D) Pfam structures
Others
PDB RCSB PDB; PDBe; PDBj
Treatment
Inhibitor-resistant β-lactamases PDBsum structure summary

AmpC-type β-lactamases (Class C)

Carbapenemases β-lactamase
IMP-type carbapenemases (metallo-β-
lactamases) (Class B)
VIM (Verona integron-encoded metallo-β-
lactamase) (Class B)
OXA (oxacillinase) group of β-lactamases (Class Action of β-lactamase and decarboxylation of
D)
the intermediate
KPC (K. pneumoniae carbapenemase) (Class A)
CMY (Class C) Identifiers
SME (Serratia marcescens Enzymes), IMI EC number 3.5.2.6
(IMIpenem-hydrolysing β-lactamase), NMC and
CcrA CAS number 9073-60-3
NDM-1 (New Delhi metallo-β-lactamase) (Class
B) Databases

Treatment of ESBL/AmpC/carbapenemases
IntEnz IntEnz view
General overview BRENDA BRENDA entry
According to genes
 ESBLs ExPASy NiceZyme view
Inhibitor-Resistant β-lactamases
KEGG KEGG entry
AmpC
Carbapenemases MetaCyc metabolic pathway
According to species PRIAM profile
Escherichia coli or Klebsiella
PDB structures RCSB PDB PDBe PDBsum
Pseudomonas aeruginosa
Gene Ontology AmiGO / QuickGO
Detection
Evolution Search

Etymology PMC articles

See also PubMed articles

References NCBI proteins
External links

Structure
The structure of a Streptomyces β-lactamase is given by1BSG.

Penicillinase
Penicillinase is a specific type of β-lactamase, showing specificity for penicillins,
again by hydrolysing the β-lactam ring. Molecular weights of the various
penicillinases tend to cluster near 50 kiloDaltons.

Penicillinase was the first β-lactamase to be identified. It was first isolated by

Abraham and Chain in 1940 from Gram-negative E. coli even before penicillin
entered clinical use,[2] but penicillinase production quickly spread to bacteria that
previously did not produce it or produced it only rarely. Penicillinase-resistant beta-
lactams such as methicillin were developed, but there is now widespread resistance
to even these. Core structure of penicillins (top) and
cephalosporins (bottom). β-lactam
ring in red.
Resistance in Gram-negative bacteria
Among Gram-negative bacteria, the emergence of resistance to expanded-spectrum
cephalosporins has been a major concern. It appeared initially in a limited number of bacterial species (E. cloacae, C. freundii, S.
marcescens, and P. aeruginosa) that could mutate to hyperproduce their chromosomal class C β-lactamase. A few years later,
resistance appeared in bacterial species not naturally producing AmpC enzymes (K. pneumoniae, Salmonella spp., P. mirabilis) due
to the production of TEM- or SHV-type ESBLs (extended spectrum beta lactamases). Characteristically, such resistance has included
oxyimino- (for exampleceftizoxime, cefotaxime, ceftriaxone, and ceftazidime, as well as the oxyimino-monobactam aztreonam), but
not 7-alpha-methoxy-cephalosporins(cephamycins; in other words, cefoxitin and cefotetan); has been blocked by inhibitors such as
clavulanate, sulbactam or tazobactam and did not involve carbapenems and temocillin. Chromosomal-mediated AmpC β-lactamases
represent a new threat, since they confer resistance to 7-alpha-methoxy-cephalosporins(cephamycins) such as cefoxitin or cefotetan
but are not affected by commercially available β-lactamase inhibitors, and can, in strains with loss of outer membrane porins, provide
resistance to carbapenems.[3]

Extended-spectrum beta-lactamase (ESBL)

Members of the family commonly express plasmid-encoded β-lactamases (e.g.,
TEM-1, TEM-2, and SHV-1), which confer resistance to penicillins but not to
expanded-spectrum cephalosporins. In the mid-1980s, a new group of enzymes, the
extended-spectrum β-lactamases (ESBLs), was detected (first detected in 1979).[4]
The prevalence of ESBL-producing bacteria have been gradually increasing in acute
care hospitals.[5] ESBLs are beta-lactamases that hydrolyze extended-spectrum
cephalosporins with an oxyimino side chain. These cephalosporins include
cefotaxime, ceftriaxone, and ceftazidime, as well as the oxyimino-monobactam
aztreonam. Thus ESBLs confer multi-resistance to these antibiotics and related
oxyimino-beta lactams. In typical circumstances, they derive from genes for TEM-1,
TEM-2, or SHV-1 by mutations that alter the amino acid configuration around the Escherichia coli bacteria on the right
active site of these β-lactamases. A broader set of β-lactam antibiotics are are sensitive to two beta-lactam
susceptible to hydrolysis by these enzymes. An increasing number of ESBLs not of antibiotics, and do not grow in the
semi-circular regions surrounding the
TEM or SHV lineage have recently been described.[6] The ESBLs are frequently
antibiotics. E. coli bacteria on the left
plasmid encoded. Plasmids responsible for ESBL production frequently carry genes are resistant to beta-lactam
encoding resistance to other drug classes (for example, aminoglycosides). Therefore, antibiotics, and grow next to one
antibiotic options in the treatment of ESBL-producing organisms are extremely antibiotic (bottom) and are less
limited. Carbapenems are the treatment of choice for serious infections due to inhibited by another antibiotic (top).
ESBL-producing organisms, yet carbapenem-resistant (primarily ertapenem
resistant) isolates have recently been reported. ESBL-producing organisms may
appear susceptible to some extended-spectrum cephalosporins. However, treatment with such antibiotics has been associated with
high failure rates.

Types

TEM beta-lactamases (class A)

TEM-1 is the most commonly encountered beta-lactamase in Gram-negative bacteria. Up to 90% of ampicillin resistance in E. coli is
due to the production of TEM-1.[7] Also responsible for the ampicillin and penicillin resistance that is seen in H. influenzae and N.
gonorrhoeae in increasing numbers. Although TEM-type beta-lactamases are most often found in E. coli and K. pneumoniae, they
are also found in other species of Gram-negative bacteria with increasing frequency. The amino acid substitutions responsible for the
extended-spectrum beta lactamase (ESBL) phenotype cluster around the active site of the enzyme and change its configuration,
allowing access to oxyimino-beta-lactam substrates. Opening the active site to beta-lactam substrates also typically enhances the
susceptibility of the enzyme to β-lactamase inhibitors, such as clavulanic acid. Single amino acid substitutions at positions 104, 164,
238, and 240 produce the ESBL phenotype, but ESBLs with the broadest spectrum usually have more than a single amino acid
substitution. Based upon different combinations of changes, currently 140 TEM-type enzymes have been described. TEM-10, TEM-
12, and TEM-26 are among the most common in the United States.[8][9][10] The term TEM comes from the name of the Athenian
[11]
patient (Temoniera) from which the isolate was recovered in 1963.

SHV beta-lactamases (class A)

SHV-1 shares 68 percent of its amino acids with TEM-1 and has a similar overall structure. The SHV-1 beta-lactamase is most
commonly found in K. pneumoniae and is responsible for up to 20% of the plasmid-mediated ampicillin resistance in this species.
ESBLs in this family also have amino acid changes around the active site, most commonly at positions 238 or 238 and 240. More
than 60 SHV varieties are known. SHV-5 and SHV-12 are among the most common.[8]

CTX-M beta-lactamases (class A)

These enzymes were named for their greater activity against cefotaxime than other oxyimino-beta-lactam substrates (e.g.,
ceftazidime, ceftriaxone, or cefepime). Rather than arising by mutation, they represent examples of plasmid acquisition of beta-
lactamase genes normally found on the chromosome of Kluyvera species, a group of rarely pathogenic commensal organisms. These
enzymes are not very closely related to TEM or SHV beta-lactamases in that they show only approximately 40% identity with these
two commonly isolated beta-lactamases. More than 80 CTX-M enzymes are currently known. Despite their name, a few are more
active on ceftazidime than cefotaxime. They have mainly been found in strains of Salmonella enterica serovar Typhimurium and E.
coli, but have also been described in other species of Enterobacteriaceae and are the predominant ESBL type in parts of South
America. (They are also seen in eastern Europe) CTX-M-14, CTX-M-3, and CTX-M-2 are the most widespread. CTX-M-15 is
currently (2006) the most widespread type in E. coli the UK and is widely prevalent in the community.[12] An example of beta-
lactamase CTX-M-15, along with ISEcp1, has been found to have recently transposed onto the chromosome of Klebsiella
pneumoniae ATCC BAA-2146.[13]

OXA beta-lactamases (class D)

OXA beta-lactamases were long recognized as a less common but also plasmid-mediated beta-lactamase variety that could hydrolyze
oxacillin and related anti-staphylococcal penicillins. These beta-lactamases differ from the TEM and SHV enzymes in that they
belong to molecular class D and functional group 2d . The OXA-type beta-lactamases confer resistance to ampicillin and cephalothin
and are characterized by their high hydrolytic activity against oxacillin and cloxacillin and the fact that they are poorly inhibited by
clavulanic acid. Amino acid substitutions in OXA enzymes can also give the ESBL phenotype. While most ESBLs have been found
in E. coli, K. pneumoniae, and other Enterobacteriaceae, the OXA-type ESBLs have been found mainly in P. aeruginosa. OXA-type
ESBLs have been found mainly in Pseudomonas aeruginosa isolates from Turkey and France. The OXA beta-lactamase family was
originally created as a phenotypic rather than a genotypic group for a few beta-lactamases that had a specific hydrolysis profile.
Therefore, there is as little as 20% sequence homology among some of the members of this family. However, recent additions to this
family show some degree of homology to one or more of the existing members of the OXA beta-lactamase family. Some confer
resistance predominantly to ceftazidime, but OXA-17 confers greater resistance to cefotaxime and cefepime than it does resistance to
ceftazidime.

Others
Other plasmid-mediated ESBLs, such as PER, VEB, GES, and IBC beta-lactamases, have been described but are uncommon and
have been found mainly in P. aeruginosa and at a limited number of geographic sites. PER-1 in isolates in Turkey, France, and Italy;
VEB-1 and VEB-2 in strains from Southeast Asia; and GES-1, GES-2, and IBC-2 in isolates from South Africa, France, and Greece.
PER-1 is also common in multiresistant acinetobacter species in Korea and Turkey. Some of these enzymes are found in
Enterobacteriaceae as well, whereas other uncommon ESBLs (such as BES-1, IBC-1, SFO-1, and TLA-1) have been found only in
Enterobacteriaceae.

Treatment
While ESBL-producing organisms were previously associated with hospitals and institutional care, these organisms are now
increasingly found in the community. CTX-M-15-positive E. coli are a cause of community-acquiredurinary infections in the UK,[12]
and tend to be resistant to all oral β-lactam antibiotics, as well as quinolones and sulfonamides. Treatment options may include
nitrofurantoin, fosfomycin, mecillinam and chloramphenicol. In desperation, once-daily ertapenem or gentamicin injections may also
be used.

Inhibitor-resistant β-lactamases
Although the inhibitor-resistant β-lactamases are not ESBLs, they are often discussed with ESBLs because they are also derivatives
of the classical TEM- or SHV-type enzymes. These enzymes were at first given the designation IRT for inhibitor-resistant TEM β-
lactamase; however, all have subsequently been renamed with numerical TEM designations. There are at least 19 distinct inhibitor-
resistant TEM β-lactamases. Inhibitor-resistant TEM β-lactamases have been found mainly in clinical isolates of E. coli, but also
some strains of K. pneumoniae, Klebsiella oxytoca, P. mirabilis, and Citrobacter freundii. Although the inhibitor-resistant TEM
variants are resistant to inhibition by clavulanic acid and sulbactam, thereby showing clinical resistance to the beta-lactam—
lactamase inhibitor combinations of amoxicillin-clavulanate (co-amoxiclav), ticarcillin-clavulanate (co-ticarclav), and
ampicillin/sulbactam, they normally remain susceptible to inhibition by tazobactam and subsequently the combination of
piperacillin/tazobactam, although resistance has been described. This is no longer a primarily European epidemiology, it is found in
[9]
northern parts of America often and should be tested for with complex UTI's.

AmpC-type β-lactamases (Class C)

AmpC type β-lactamases are commonly isolated from extended-spectrum cephalosporin-resistant Gram-negative bacteria. AmpC β-
lactamases (also termed class C or group 1) are typically encoded on the chromosome of many Gram-negative bacteria including
Citrobacter, Serratia and Enterobacter species where its expression is usually inducible; it may also occur on Escherichia coli but is
not usually inducible, although it can be hyperexpressed. AmpC type β-lactamases may also be carried on plasmids.[3] AmpC β-
lactamases, in contrast to ESBLs, hydrolyse broad and extended-spectrum cephalosporins (cephamycins as well as to oxyimino-β-
lactams) but are not inhibited by β-lactamase inhibitors such as clavulanic acid. AmpC-type β-lactamase organisms are often
clinically grouped through the acronym, "SP
ACE": Serratia, Pseudomonas or Proteus, Acinetobacter, Citrobacter, and Enterobacter.

Carbapenemases
Carbapenems are famously stable to AmpC β-lactamases and extended-spectrum-β-lactamases.Carbapenemases are a diverse group
of β-lactamases that are active not only against the oxyimino-cephalosporins and cephamycins but also against the carbapenems.
Aztreonam is stable to the metallo-β-lactamases, but many IMP and VIM producers are resistant, owing to other mechanisms.
Carbapenemases were formerly believed to derive only from classes A, B, and D, but a class C carbapenemase has been described.

IMP-type carbapenemases (metallo-β-lactamases) (Class B)

Plasmid-mediated IMP-type carbapenemases, 19 varieties of which are currently known, became established in Japan in the 1990s
both in enteric Gram-negative organisms and in Pseudomonas and Acinetobacter species. IMP enzymes spread slowly to other
countries in the Far East, were reported from Europe in 1997, and have been found in Canada and Brazil.

VIM (Verona integron-encoded metallo-β-lactamase) (Class B)

A second growing family of carbapenemases, the VIM family, was reported from Italy in 1999 and now includes 10 members, which
have a wide geographic distribution in Europe, South America, and the Far East and have been found in the United States. VIM-1
was discovered in P. aeruginosa in Italy in 1996; since then, VIM-2 - now the predominant variant - was found repeatedly in Europe
and the Far East; VIM-3 and -4 are minor variants of VIM-2 and -1, respectively. VIM enzymes occur mostly in P. aeruginosa, also
P. putida and, very rarely, Enterobacteriaceae.

Amino acid sequence diversity is up to 10% in the VIM family, 15% in the IMP family, and 70% between VIM and IMP. Enzymes of
both the families, nevertheless, are similar. Both are integron-associated, sometimes within plasmids. Both hydrolyse all β-lactams
except monobactams, and evade all β-lactam inhibitors. The VIM enzymes are among the most widely distributed MBLs, with >40
VIM variants having been reported. Biochemical and biophysical studies revealed that VIM variants have only small variations in
[14]
their kinetic parameters but substantial differences in their thermal stabilities and inhibition profiles.

OXA (oxacillinase) group of β-lactamases (Class D)

The OXA group of β-lactamases occur mainly in Acinetobacter species and are divided into two clusters. OXA carbapenemases
hydrolyse carbapenems very slowlyin vitro, and the high MICs seen for some Acinetobacter hosts (>64 mg/L) may reflect secondary
mechanisms. They are sometimes augmented in clinical isolates by additional resistance mechanisms, such as impermeability or
ficiency towards penicillins and cephalosporins.[15]
efflux. OXA carbapenemases also tend to have a reduced hydrolytic ef

KPC (K. pneumoniae carbapenemase) (Class A)

A few class A enzymes, most noted the plasmid-mediated KPC enzymes, are effective carbapenemases as well. Ten variants, KPC-2
through KPC-11 are known, and they are distinguished by one or two amino acid substitutions (KPC-1 was re-sequenced in 2008 and
found to be 100% homologous to published sequences of KPC-2). KPC-1 was found in North Carolina, KPC-2 in Baltimore and
KPC-3 in New York. They have only 45% homology with SME and NMC/IMI enzymes and, unlike them, can be encoded by self-
transmissible plasmids.

As of February 2009, the class A Klebsiella pneumoniae carbapenemase (KPC) globally has been the most common carbapenemase,
and was first detected in 1996 in North Carolina, USA.[16] A 2010 publication indicated that KPC producing Enterobacteriaceae
were becoming common in the United States.[17]

CMY (Class C)
The first class C carbapenemase was described in 2006 and was isolated from a virulent strain of Enterobacter aerogenes.[18] It is
[19]
carried on a plasmid, pYMG-1, and is therefore transmissible to other bacterial strains.

SME (Serratia marcescens Enzymes), IMI (IMIpenem-hydrolysing β-lactamase), NMC and CcrA
In general, these are of little clinical significance.

CcrA (CfiA). Its gene occurs in ca. 1-3% of B. fragilis isolates, but fewer produce the enzyme since expression demands appropriate
migration of an insertion sequence. CcrA was known before imipenem was introduced, and producers have shown little subsequent
increase.

NDM-1 (New Delhi metallo-β-lactamase) (Class B)

Originally described fromNew Delhi in 2009, this gene is now widespread in Escherichia coli and Klebsiella pneumoniaefrom India
and Pakistan. As of mid-2010, NDM-1 carrying bacteria have been introduced to other countries (including the United States and
UK), most probably due to the large number of tourists travelling the globe, who may have picked up the strain from the
environment, as strains containing the NDM-1 gene have been found in environmental samples in India.[20] NDM have several
variants which share different properties.[21]

Treatment of ESBL/AmpC/carbapenemases

General overview
In general, an isolate is suspected to be an ESBL producer when it shows in vitro susceptibility to the second-generation
cephalosporins (cefoxitin, cefotetan) but resistance to the third-generation cephalosporins and to aztreonam. Moreover, one should
suspect these strains when treatment with these agents for Gram-negative infections fails despite reported in vitro susceptibility. Once
an ESBL-producing strain is detected, the laboratory should report it as "resistant" to all penicillins, cephalosporins, and aztreonam,
even if it is tested (in vitro) as susceptible. Associated resistance to aminoglycosides and trimethoprim-sulfamethoxazole, as well as
high frequency of co-existence of fluoroquinolone resistance, creates problems. Beta-lactamase inhibitors such as clavulanate,
sulbactam, and tazobactam in vitro inhibit most ESBLs, but the clinical effectiveness of beta-lactam/beta-lactamase inhibitor
combinations cannot be relied on consistently for therapy. Cephamycins (cefoxitin and cefotetan) are not hydrolyzed by majority of
ESBLs, but are hydrolyzed by associated AmpC-type β-lactamase. Also, β-lactam/β-lactamase inhibitor combinations may not be
effective against organisms that produce AmpC-type β-lactamase. Sometimes these strains decrease the expression of outer
membrane proteins, rendering them resistant to cephamycins. In vivo studies have yielded mixed results against ESBL-producing K.
pneumoniae. (Cefepime, a fourth-generation cephalosporin, has demonstrated in vitro stability in the presence of many ESBL/AmpC
strains.) Currently, carbapenems are, in general, regarded as the preferred agent for treatment of infections due to ESBL-producing
organisms. Carbapenems are resistant to ESBL-mediated hydrolysis and exhibit excellent in vitro activity against strains of
Enterobacteriaceae expressing ESBLs.
According to genes

ESBLs
Strains producing only ESBLs are susceptible to cephamycins and carbapenems in vitro and show little if any inoculum effect with
these agents.

For organisms producing TEM and SHV type ESBLs, apparent in vitro sensitivity to cefepime and to piperacillin/tazobactam is
common, but both drugs show an inoculum effect, with diminished susceptibility as the size of the inoculum is increased from 105 to
107 organisms.

Strains with some CTX-M–type and OXA-type ESBLs are resistant tocefepime on testing, despite the use of a standard inoculum.

Inhibitor-Resistant β-lactamases
Although the inhibitor-resistant TEM variants are resistant to inhibition by clavulanic acid and sulbactam, thereby showing clinical
resistance to the beta-lactam—beta lactamase inhibitor combinations of amoxicillin-clavulanate (Co-amoxiclav), ticarcillin-
clavulanate, and ampicillin/sulbactam, they remain susceptible to inhibition by tazobactam and subsequently the combination of
piperacillin/tazobactam.

AmpC
AmpC-producing strains are typically resistant to oxyimino-beta lactams and to cephamycins and are susceptible to carbapenems;
however, diminished porin expression can make such a strain carbapenem-resistant as well.

Carbapenemases
Strains with IMP-, VIM-, and OXA-type carbapenemases usually remain susceptible. Resistance to non-beta-lactam antibiotics is
common in strains making any of these enzymes, such that alternative options for non-beta-lactam therapy need to be determined by
direct susceptibility testing. Resistance tofluoroquinolones and aminoglycosides is especially high.

According to species

Escherichia coli or Klebsiella

For infections caused by ESBL-producing Escherichia coli or Klebsiella species, treatment with imipenem or meropenem has been
associated with the best outcomes in terms of survival and bacteriologic clearance. Cefepime and piperacillin/tazobactam have been
less successful. Ceftriaxone, cefotaxime, and ceftazidime have failed even more often, despite the organism's susceptibility to the
antibiotic in vitro. Several reports have documented failure of cephamycin therapy as a result of resistance due to porin loss. Some
patients have responded to aminoglycoside or quinolone therapy, but, in a recent comparison of ciprofloxacin and imipenem for
bacteremia involving an ESBL-producingK. pneumoniae, imipenem produced the better outcome

Pseudomonas aeruginosa
There have been few clinical studies to define the optimal therapy for infections caused by ESBL producing Pseudomonas
aeruginosa strains.

Detection
Beta-lactamase enzymatic activity can be detected using nitrocefin, a chromogenic cephalosporin substrate which changes color from
[22]
yellow to red upon beta-lactamase mediated hydrolysis.
Evolution
Beta-lactamases are ancient bacterial enzymes. The class B beta-lactamases (the metallo-beta-lactamases) are divided into three
subclasses: B1, B2 and B3. Subclasses B1 and B2 are theorized to have evolved about one billion years ago and subclass B3s is
[23]
theorized to have evolved before the divergence of the Gram-positive and Gram-negative eubacteria about two billion years ago.

The other three groups are serine enzymes that show little homology to each other. Structural studies have shown that groups A and
D are sister taxa and that group C diverged before A and D.[24] These serine-based enzymes, like the group B betalactamases, are of
[25]
ancient origin and are theorized to have evolved about two billion years ago.

The OXA group (in class D) in particular is theorized to have evolved on chromosomes and moved to plasmids on at least two
separate occasions.[26]

Etymology
The "β" (beta) refers to the nitrogen's position on the second carbon in the ring. Lactam is a portmanteau of lactone (from the Latin
lactis, milk, since lactic acid was isolated from soured milk) and amide. The suffix -ase, indicating an enzyme, is derived from
[27]
diastase (from the Greek diastasis, "separation"), the first enzyme discovered in 1833 by Payen and Persoz.

See also
ESBL-producing E. coli
Nitrocefin
β-lactamase inhibitor

References
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(https://www.ncbi.nl
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External links
Online ESBL genotyping tool (EGT)
Online Amino Acid Sequences for ESBL enzymes
beta-Lactamases at the US National Library of MedicineMedical Subject Headings(MeSH)

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