| Gene name | Length | Location | Length of alignment | Identity (%) | Coverage (%) | E-value |
|---|---|---|---|---|---|---|
| repA | 1101 | 1 - 1101 (+) | 1101 | 100 | 100 | 0 |
| ORF1832 | 5499 | 62399 - 67897 (+) | 5499 | 100 | 100 | 0 |
| RHS1 | 4254 | 134485 - 138738 (+) | 4254 | 100 | 100 | 0 |
| AriB | 1156 | 30400 - 31555 (+) | 1156 | 100 | 44 | 0 |
| AriB | 640 | 22856 - 23495 (+) | 640 | 100 | 24 | 0 |
| Type match | Model name | Model type | Location | E-value | Identity | ||||
|---|---|---|---|---|---|---|---|---|---|
| Strict | floR | protein homolog model | 24392 - 25606(+) | 0 | 99.75 % | ||||
|
AMR Gene Family
Directed pumping of antibiotic out of a cell to confer resistance. Major facilitator superfamily (MFS) transporters and ABC transporters comprise the two largest and most functionally diverse of the transporter superfamilies. However, MFS transporters are distinct from ABC transporters in both their primary sequence and structure and in the mechanism of energy coupling. As secondary transporters they are, like RND and SMR transporters, energized by the electrochemical proton gradient.
Antibiotic
Chloramphenicol is a bacteriostatic antimicrobial originally derived from the bacterium Streptomyces venezuelae. It was the first antibiotic to be manufactured synthetically on a large scale. It functions by inhibiting peptidyl transferase activity of the bacterial ribosome, binding to A2451 and A2452 residues in the 23S rRNA of the 50S ribosomal subunit and preventing peptide bond formation.
Antibiotic
Florfenicol is a fluorine derivative of chloramphenicol, where the nitro group (-NO2) is substituted by a sulfomethyl group (-SO2CH3) and the hydroxyl group (-OH), by a fluorine group (-F). The action mechanism is the same as chloramphenicol's, where the antibiotic binds to the 23S RNA of the 50S subunit of bacterial ribosomes to inhibit protein synthesis.
Drug Class
Phenicols are broad spectrum bacteriostatic antibiotics acting on bacterial protein synthesis. More specifically, the phenicols block peptide elongation by binding to the peptidyltansferase centre of the 70S ribosome.
Efflux Component
Efflux proteins that pump antibiotic out of a cell to confer resistance.
Resistance Mechanism
Antibiotic resistance via the transport of antibiotics out of the cell.
|
|||||||||
| Strict | tet(A) | protein homolog model | 26206 - 27405(-) | 0 | 99.75 % | ||||
|
AMR Gene Family
Directed pumping of antibiotic out of a cell to confer resistance. Major facilitator superfamily (MFS) transporters and ABC transporters comprise the two largest and most functionally diverse of the transporter superfamilies. However, MFS transporters are distinct from ABC transporters in both their primary sequence and structure and in the mechanism of energy coupling. As secondary transporters they are, like RND and SMR transporters, energized by the electrochemical proton gradient.
Antibiotic
Tetracycline is a broad-spectrum polyketide antibiotic produced by many Streptomyces. It works by inhibiting action of the prokaryotic 30S ribosome.
Drug Class
These antibiotics are derived from tetracycline, a polyketide antibiotic that inhibits the 30S subunit of bacterial ribosomes.
Efflux Component
Efflux proteins that pump antibiotic out of a cell to confer resistance.
Resistance Mechanism
Antibiotic resistance via the transport of antibiotics out of the cell.
|
|||||||||
| Strict | APH(6)-Id | protein homolog model | 28741 - 29577(-) | 0 | 99.64 % | ||||
|
AMR Gene Family
Phosphorylation of streptomycin on the hydroxyl group at position 6
Antibiotic
Streptomycin is an aminoglycoside antibiotic used to treat different types of bacterial infections. Streptomycin works by binding to the bacterial 30S ribosomal subunit, causing misreading of mRNA and leaving the bacterium unable to synthesize proteins vital to its growth.
Drug Class
Aminoglycosides are a group of antibiotics that are mostly effective against Gram-negative bacteria. These molecules consist of aminated sugars attached to a dibasic cyclitol. Aminoglycosides work by binding to the bacterial 30S ribosomal subunit (some work by binding to the 50S subunit), inhibiting the translocation of the peptidyl-tRNA from the A-site to the P-site and also causing misreading of mRNA, leaving the bacterium unable to synthesize proteins vital to its growth.
Resistance Mechanism
Enzymatic inactivation of antibiotic to confer drug resistance.
|
|||||||||
| Strict | APH(3'')-Ib | protein homolog model | 29577 - 30380(-) | 0 | 99.63 % | ||||
|
AMR Gene Family
Phosphorylation of streptomycin on the hydroxyl group at position 3''
Antibiotic
Streptomycin is an aminoglycoside antibiotic used to treat different types of bacterial infections. Streptomycin works by binding to the bacterial 30S ribosomal subunit, causing misreading of mRNA and leaving the bacterium unable to synthesize proteins vital to its growth.
Drug Class
Aminoglycosides are a group of antibiotics that are mostly effective against Gram-negative bacteria. These molecules consist of aminated sugars attached to a dibasic cyclitol. Aminoglycosides work by binding to the bacterial 30S ribosomal subunit (some work by binding to the 50S subunit), inhibiting the translocation of the peptidyl-tRNA from the A-site to the P-site and also causing misreading of mRNA, leaving the bacterium unable to synthesize proteins vital to its growth.
Resistance Mechanism
Enzymatic inactivation of antibiotic to confer drug resistance.
|
|||||||||
| Perfect | sul2 | protein homolog model | 30441 - 31256(-) | 0 | 100 % | ||||
|
AMR Gene Family
The sul genes encode forms of dihydropteroate synthase that confer resistance to sulfonamide.
Antibiotic
Sulfadiazine is a potent inhibitor of dihydropteroate synthase, interfering with the tetrahydrofolic biosynthesis pathway. Tetrahydrofolic acid is essential for folate synthesis, a precursor to many nucleotides and amino acids.
Antibiotic
Sulfadimidine is an alkaline sulfonamide antibiotic that inhibits dihydropteroate synthase, and enzyme in the tetrahydrofolic acid biosynthesis pathway. This interferes with the production of folate, which is a precursor to many amino acids and nucleotides.
Antibiotic
Sulfadoxine is an inhibitor of dihydropteroate synthase, interfering with the tetrahydrofolic biosynthesis pathway. Tetrahydrofolic acid is essential for folate synthesis, a precursor to many nucleotides and amino acids.
Antibiotic
Sulfamethoxazole is a sulfonamide antibiotic usually taken with trimethoprim, a diaminopyrimidine antibiotic. Sulfamethoxazole inhibits dihydropteroate synthase, essential to tetrahydrofolic acid biosynthesis. This pathway generates compounds used in the synthesis of many amino acids and nucleotides.
Antibiotic
Sulfisoxazole is an inhibitor of dihydropteroate synthase, interfering with the tetrahydrofolic biosynthesis pathway. Tetrahydrofolic acid is essential for folate synthesis, a precursor to many nucleotides and amino acids.
Antibiotic
Sulfacetamide is a very soluable sulfonamide antibiotic previously used to treat urinary tract infections. Its relatively low activity and toxicity to those with Stevens-Johnson syndrome have reduced its use and availability.
Antibiotic
Mafenide is a sulfonamide used topically for treating burns.
Antibiotic
Sulfasalazine is a derivative of the early sulfonamide sulfapyridine (salicylazosulfapyridine). It was developed to increase water solubility and is taken orally for ulcerative colitis.
Antibiotic
Sulfamethizole is a short-acting sulfonamide that inhibits dihydropteroate synthetase.
Drug Class
Sulfonamides are broad spectrum, synthetic antibiotics that contain the sulfonamide group. Sulfonamides inhibit dihydropteroate synthase, which catalyzes the conversion of p-aminobenzoic acid to dihydropteroic acid as part of the tetrahydrofolic acid biosynthetic pathway. Tetrahydrofolic acid is essential for folate synthesis, a precursor of many nucleotides and amino acids. Many sulfamides are taken with trimethoprim, an inhibitor of dihydrofolate reductase, also disturbing the trihydrofolic acid synthesis pathway.
Resistance Mechanism
Replacement or substitution of antibiotic action target, which process will result in antibiotic resistance.
|
|||||||||
| Perfect | CMY-16 | protein homolog model | 59597 - 60742(+) | 0 | 100 % | ||||
|
AMR Gene Family
CMY beta-lactamases are plasmid-mediated class C beta-lactamases that encodes for resistance to cephamycins.
Drug Class
Cephamycins are a group of beta-lactam antibiotics, very similar to cephalosporins. Together with cephalosporins, they form a sub-group of antibiotics known as cephems. Cephamycins are bactericidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms. The 7-alpha-methoxy group increases resistance to beta-lactamases.
Resistance Mechanism
Enzymatic inactivation of antibiotic to confer drug resistance.
|
|||||||||
| Strict | dfrA14 | protein homolog model | 113344 - 113817(+) | 2.51244e-118 | 98.73 % | ||||
|
AMR Gene Family
Alternative dihydropteroate synthase dfr present on plasmids produces alternate proteins that are less sensitive to trimethoprim from inhibiting its role in folate synthesis, thus conferring trimethoprim resistance.
Antibiotic
Trimethoprim is a synthetic 5-(3,4,5- trimethoxybenzyl) pyrimidine inhibitor of dihydrofolate reductase, inhibiting synthesis of tetrahydrofolic acid. Tetrahydrofolic acid is an essential precursor in the de novo synthesis of the DNA nucleotide thymidine. Trimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections in combination with sulfamethoxazole, a sulfonamide antibiotic.
Drug Class
Diaminopyrimidines are a class of organic compounds containing a pyrimidine ring substituted by two amine groups. They are inhibitors of dihydrofolate reductase, an enzyme critical for DNA synthesis.
Resistance Mechanism
Replacement or substitution of antibiotic action target, which process will result in antibiotic resistance.
|
|||||||||
| Perfect | arr-2 | protein homolog model | 113928 - 114380(+) | 2.33764e-112 | 100 % | ||||
|
AMR Gene Family
Enzyme responsible for the ADP-ribosylative inactivation of rifampin at the 23-OH position using NAD+.
Antibiotic
Rifampin is a semi-synthetic rifamycin, and inhibits RNA synthesis by binding to RNA polymerase. Rifampin is the mainstay agent for the treatment of tuberculosis, leprosy and complicated Gram-positive infections.
Antibiotic
Rifaximin is a semi-synthetic rifamycin used to treat traveller's diarrhea. Rifaximin inhibits RNA synthesis by binding to the beta subunit of bacterial RNA polymerase.
Antibiotic
Rifabutin is a semisynthetic rifamycin used in tuberculosis therapy. It inhibits DNA-dependent RNA synthesis.
Antibiotic
Rifapentine is a semisynthetic rifamycin that inhibits DNA-dependent RNA synthesis. It is often used in the treatment of tuberculosis and leprosy.
Drug Class
Rifamycin antibiotics are a group of broad-spectrum ansamycin antibiotics that inhibit bacterial RNA polymerase by binding to a highly conserved region, blocking the oligonucleotide exit tunnel, and preventing the extension of nascent mRNAs.
Resistance Mechanism
Enzymatic inactivation of antibiotic to confer drug resistance.
|
|||||||||
| Perfect | cmlA5 | protein homolog model | 114701 - 115960(+) | 0 | 100 % | ||||
|
AMR Gene Family
Directed pumping of antibiotic out of a cell to confer resistance. Major facilitator superfamily (MFS) transporters and ABC transporters comprise the two largest and most functionally diverse of the transporter superfamilies. However, MFS transporters are distinct from ABC transporters in both their primary sequence and structure and in the mechanism of energy coupling. As secondary transporters they are, like RND and SMR transporters, energized by the electrochemical proton gradient.
Antibiotic
Chloramphenicol is a bacteriostatic antimicrobial originally derived from the bacterium Streptomyces venezuelae. It was the first antibiotic to be manufactured synthetically on a large scale. It functions by inhibiting peptidyl transferase activity of the bacterial ribosome, binding to A2451 and A2452 residues in the 23S rRNA of the 50S ribosomal subunit and preventing peptide bond formation.
Drug Class
Phenicols are broad spectrum bacteriostatic antibiotics acting on bacterial protein synthesis. More specifically, the phenicols block peptide elongation by binding to the peptidyltansferase centre of the 70S ribosome.
Efflux Component
Efflux proteins that pump antibiotic out of a cell to confer resistance.
Resistance Mechanism
Antibiotic resistance via the transport of antibiotics out of the cell.
|
|||||||||
| Perfect | OXA-10 | protein homolog model | 116225 - 117025(+) | 0 | 100 % | ||||
|
AMR Gene Family
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. 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.
Drug Class
Cephalosporins are a class of beta-lactam antibiotics, containing the beta-lactam ring fused with a dihydrothiazolidine ring. Together with cephamycins they belong to a sub-group called cephems. Cephalosporin are bactericidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms.
Drug Class
Penams, often referred to as penicillins, are a group of antibiotics derived from Penicillium fungi. Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases such as syphilis and Staphylococcus infections. Penicillins are still widely used today, though many types of bacteria are now resistant. All penicillins are beta-lactam antibiotics in the penam sub-group, and are used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms.
Resistance Mechanism
Enzymatic inactivation of antibiotic to confer drug resistance.
|
|||||||||
| Strict | ANT(3'')-IIa | protein homolog model | 117018 - 117833(+) | 0 | 99.63 % | ||||
|
AMR Gene Family
Nucleotidylylation of streptomycin at the hydroxyl group at position 3''
Drug Class
Aminoglycosides are a group of antibiotics that are mostly effective against Gram-negative bacteria. These molecules consist of aminated sugars attached to a dibasic cyclitol. Aminoglycosides work by binding to the bacterial 30S ribosomal subunit (some work by binding to the 50S subunit), inhibiting the translocation of the peptidyl-tRNA from the A-site to the P-site and also causing misreading of mRNA, leaving the bacterium unable to synthesize proteins vital to its growth.
Resistance Mechanism
Enzymatic inactivation of antibiotic to confer drug resistance.
|
|||||||||
| Perfect | sul1 | protein homolog model | 118338 - 119177(+) | 0 | 100 % | ||||
|
AMR Gene Family
The sul genes encode forms of dihydropteroate synthase that confer resistance to sulfonamide.
Antibiotic
Sulfadiazine is a potent inhibitor of dihydropteroate synthase, interfering with the tetrahydrofolic biosynthesis pathway. Tetrahydrofolic acid is essential for folate synthesis, a precursor to many nucleotides and amino acids.
Antibiotic
Sulfadimidine is an alkaline sulfonamide antibiotic that inhibits dihydropteroate synthase, and enzyme in the tetrahydrofolic acid biosynthesis pathway. This interferes with the production of folate, which is a precursor to many amino acids and nucleotides.
Antibiotic
Sulfadoxine is an inhibitor of dihydropteroate synthase, interfering with the tetrahydrofolic biosynthesis pathway. Tetrahydrofolic acid is essential for folate synthesis, a precursor to many nucleotides and amino acids.
Antibiotic
Sulfamethoxazole is a sulfonamide antibiotic usually taken with trimethoprim, a diaminopyrimidine antibiotic. Sulfamethoxazole inhibits dihydropteroate synthase, essential to tetrahydrofolic acid biosynthesis. This pathway generates compounds used in the synthesis of many amino acids and nucleotides.
Antibiotic
Sulfisoxazole is an inhibitor of dihydropteroate synthase, interfering with the tetrahydrofolic biosynthesis pathway. Tetrahydrofolic acid is essential for folate synthesis, a precursor to many nucleotides and amino acids.
Antibiotic
Sulfacetamide is a very soluable sulfonamide antibiotic previously used to treat urinary tract infections. Its relatively low activity and toxicity to those with Stevens-Johnson syndrome have reduced its use and availability.
Antibiotic
Mafenide is a sulfonamide used topically for treating burns.
Antibiotic
Sulfasalazine is a derivative of the early sulfonamide sulfapyridine (salicylazosulfapyridine). It was developed to increase water solubility and is taken orally for ulcerative colitis.
Antibiotic
Sulfamethizole is a short-acting sulfonamide that inhibits dihydropteroate synthetase.
Drug Class
Sulfonamides are broad spectrum, synthetic antibiotics that contain the sulfonamide group. Sulfonamides inhibit dihydropteroate synthase, which catalyzes the conversion of p-aminobenzoic acid to dihydropteroic acid as part of the tetrahydrofolic acid biosynthetic pathway. Tetrahydrofolic acid is essential for folate synthesis, a precursor of many nucleotides and amino acids. Many sulfamides are taken with trimethoprim, an inhibitor of dihydrofolate reductase, also disturbing the trihydrofolic acid synthesis pathway.
Resistance Mechanism
Replacement or substitution of antibiotic action target, which process will result in antibiotic resistance.
|
|||||||||
| Perfect | NDM-1 | protein homolog model | 121449 - 122261(+) | 0 | 100 % | ||||
|
Adjuvant
Clavulanic acid is a beta-lactamase inhibitor (marketed by GlaxoSmithKline, formerly Beecham) combined with penicillin group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete beta-lactamase, which otherwise inactivates most penicillins.
AMR Gene Family
NDM beta-lactamases or New Delhi metallo-beta-lactamases are class B beta-lactamases that confer resistance to a broad range of antibiotics including carbapenems, cephalosporins and penicillins.
Antibiotic
Amoxicillin is a moderate-spectrum, bacteriolytic, beta-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms. A derivative of penicillin, it has a wider range of treatment but remains relatively ineffective against Gram-negative bacteria. It is commonly taken with clavulanic acid, a beta-lactamase inhibitor. Like other beta-lactams, amoxicillin interferes with the synthesis of peptidoglycan.
Antibiotic
Ertapenem is a carbapenem antibiotic and is highly resistant to beta-lactamases like other carbapenems. It inhibits bacterial cell wall synthesis.
Antibiotic
Meropenem is an ultra-broad spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia. It is a beta-lactam and belongs to the subgroup of carbapenem, similar to imipenem and ertapenem.
Antibiotic
Imipenem is a broad-spectrum antibiotic and is usually taken with cilastatin, which prevents hydrolysis of imipenem by renal dehydropeptidase-I. It is resistant to hydrolysis by most other beta-lactamases. Notable exceptions are the KPC beta-lactamases and Ambler Class B enzymes.
Antibiotic
An antibiotic cocktail containing the beta-lactam antibiotic Amoxicillin and the beta-lactamase inhibitor Clavulanic Acid (potassium clavulanate).
Drug Class
Carbapenems are a class of beta-lactam antibiotics with a broad spectrum of antibacterial activity, and have a structure which renders them highly resistant to beta-lactamases. Carbapenem antibiotics are bactericidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms.
Drug Class
Cephalosporins are a class of beta-lactam antibiotics, containing the beta-lactam ring fused with a dihydrothiazolidine ring. Together with cephamycins they belong to a sub-group called cephems. Cephalosporin are bactericidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms.
Drug Class
Cephamycins are a group of beta-lactam antibiotics, very similar to cephalosporins. Together with cephalosporins, they form a sub-group of antibiotics known as cephems. Cephamycins are bactericidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms. The 7-alpha-methoxy group increases resistance to beta-lactamases.
Drug Class
Penams, often referred to as penicillins, are a group of antibiotics derived from Penicillium fungi. Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases such as syphilis and Staphylococcus infections. Penicillins are still widely used today, though many types of bacteria are now resistant. All penicillins are beta-lactam antibiotics in the penam sub-group, and are used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms.
Resistance Mechanism
Enzymatic inactivation of antibiotic to confer drug resistance.
|
|||||||||
| Perfect | sul1 | protein homolog model | 122561 - 123400(+) | 0 | 100 % | ||||
|
AMR Gene Family
The sul genes encode forms of dihydropteroate synthase that confer resistance to sulfonamide.
Antibiotic
Sulfadiazine is a potent inhibitor of dihydropteroate synthase, interfering with the tetrahydrofolic biosynthesis pathway. Tetrahydrofolic acid is essential for folate synthesis, a precursor to many nucleotides and amino acids.
Antibiotic
Sulfadimidine is an alkaline sulfonamide antibiotic that inhibits dihydropteroate synthase, and enzyme in the tetrahydrofolic acid biosynthesis pathway. This interferes with the production of folate, which is a precursor to many amino acids and nucleotides.
Antibiotic
Sulfadoxine is an inhibitor of dihydropteroate synthase, interfering with the tetrahydrofolic biosynthesis pathway. Tetrahydrofolic acid is essential for folate synthesis, a precursor to many nucleotides and amino acids.
Antibiotic
Sulfamethoxazole is a sulfonamide antibiotic usually taken with trimethoprim, a diaminopyrimidine antibiotic. Sulfamethoxazole inhibits dihydropteroate synthase, essential to tetrahydrofolic acid biosynthesis. This pathway generates compounds used in the synthesis of many amino acids and nucleotides.
Antibiotic
Sulfisoxazole is an inhibitor of dihydropteroate synthase, interfering with the tetrahydrofolic biosynthesis pathway. Tetrahydrofolic acid is essential for folate synthesis, a precursor to many nucleotides and amino acids.
Antibiotic
Sulfacetamide is a very soluable sulfonamide antibiotic previously used to treat urinary tract infections. Its relatively low activity and toxicity to those with Stevens-Johnson syndrome have reduced its use and availability.
Antibiotic
Mafenide is a sulfonamide used topically for treating burns.
Antibiotic
Sulfasalazine is a derivative of the early sulfonamide sulfapyridine (salicylazosulfapyridine). It was developed to increase water solubility and is taken orally for ulcerative colitis.
Antibiotic
Sulfamethizole is a short-acting sulfonamide that inhibits dihydropteroate synthetase.
Drug Class
Sulfonamides are broad spectrum, synthetic antibiotics that contain the sulfonamide group. Sulfonamides inhibit dihydropteroate synthase, which catalyzes the conversion of p-aminobenzoic acid to dihydropteroic acid as part of the tetrahydrofolic acid biosynthetic pathway. Tetrahydrofolic acid is essential for folate synthesis, a precursor of many nucleotides and amino acids. Many sulfamides are taken with trimethoprim, an inhibitor of dihydrofolate reductase, also disturbing the trihydrofolic acid synthesis pathway.
Resistance Mechanism
Replacement or substitution of antibiotic action target, which process will result in antibiotic resistance.
|
|||||||||