Drug Information

Drug (ID: DG00221) and It's Reported Resistant Information

• Name: Streptomycin
• Synonyms: Agrept; Agrimycin; Gerox; Neodiestreptopab; SRY; Strepcen; Streptomicina; Streptomycine; Streptomycinum; Streptomyzin; Liposomal Streptomycin; Streptomicina [Italian]; Streptomycin A; Streptomycin A sulfate; Streptomycin Sesquisulfate Hydrate; Streptomycin sulfate; Streptomycin sulphate; Streptomyzin [German]; Agrept (TN); Estreptomicina [INN-Spanish]; Hokko-mycin; Plantomycin (TN); Rimosidin (TN); Streptomycin & EEP; Streptomycin & Propolis; Streptomycin (INN); Streptomycin (TN); Streptomycin [INN:BAN]; Streptomycin, Sulfate Salt; AS-50 (TN); STREPTOMYCIN SULFATE (2:3) SALT; Agri-mycin-17 (TN); O-2-Deoxy-2-(methylamino)-.alpha.-L-glucopyranosyl-(1->2)-O-5-deoxy-3-C-formyl-.alpha.-L-lyxofuranosyl-(1->4)-N,N'-bis(aminoiminomethyl)-D-streptamine and Liposome; N,N'''-[(1R,2R,3S,4R,5R,6S)-4-{5-deoxy-2-O-[2-deoxy-2-(methylamino)-alpha-L-glucopyranosyl]-3-C-formyl-alpha-L-lyxofuranosyloxy}-2,5,6-trihydroxycyclohexane-1,3-diyl]diguanidine; N,N'''-[(1R,2R,3S,4R,5R,6S)-4-({5-deoxy-2-O-[2-deoxy-2-(methylamino)-alpha-L-glucopyranosyl]-3-C-formyl-alpha-L-lyxofuranosyl}oxy)-2,5,6-trihydroxycyclohexane-1,3-diyl]diguanidine; 2,4-Diguanidino-3,5,6-trihydroxycyclohexyl 5-deoxy-2-O-(2-deoxy-2-methylamino-alpha-L-glucopyranosyl)-3-C-formyl-beta-L-lyxopentanofuranoside; 2-[(1R,2R,3S,4R,5R,6S)-3-(diaminomethylideneamino)-4-[(2R,3R,4R,5S)-3-[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy-2,5,6-trihydroxycyclohexyl]guanidine; 2-[(1R,2R,3S,4R,5R,6S)-3-(diaminomethylideneamino)-4-[(2S,3S,4S,5R)-3-[(2R,3R,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy-2,5,6-trihydroxycyclohexyl]guanidine; 2-[(1S,2S,3R,4S,5S,6R)-3-(diaminomethylideneamino)-4-[(2R,3R,4R,5S)-3-[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy-2,5,6-trihydroxycyclohexyl]guanidine; 2-[(1S,4S)-5-(diaminomethylideneamino)-2-[(2R,5S)-3-[(2S,5R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy-3,4,6-trihydroxycyclohexyl]guanidine; [2-deoxy-2-(dimethylamino)-alpha-L-glucopyranosyl]-(1->2)-[5-deoxy-3-C-formyl-alpha-L-lyxofuranosyl]-(1->4)-{N',N'''-[(1,3,5/2,4,6)-2,4,5,6-tetrahydroxycyclohexane-1,3-diyl]diguanidine}
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1], [2], [3], [4], [5], [6]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (13 diseases)
  Bacteremia [ICD-11: MA15]; [7]
  Bacterial infection [ICD-11: 1A00-1C4Z]; [8]
  Cholera [ICD-11: 1A00]; [9]
  Escherichia coli intestinal infection [ICD-11: 1A03]; [10]
  HIV associated with tuberculosis [ICD-11: 1C60]; [1], [2], [3]
  Infective endocarditis [ICD-11: BB40]; [7]
  Non-tuberculous mycobacteria infection [ICD-11: 1B21]; [7]
  Salmonellosis [ICD-11: 1A09]; [11]
  Serious necrotizing pneumonia [ICD-11: CA43]; [7]
  Surgical wound infection [ICD-11: NE81]; [7]
  Toxic shock syndrome [ICD-11: 1C45]; [7]
  Tuberculosis [ICD-11: 1B10]; [12]
  Tuberculous sclerokeratitis [ICD-11: 1B12]; [13]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (7 diseases)
  Actinomycetoma [ICD-11: 1C43]; [14]
  Bacterial infection [ICD-11: 1A00-1C4Z]; [15], [16]
  Campylobacteriosis [ICD-11: 1C40]; [17]
  Escherichia coli intestinal infection [ICD-11: 1A03]; [18]
  Gram-negative bacterial infection [ICD-11: 1B74-1G40]; [19]
  Pasteurellosis [ICD-11: 1B99]; [20]
  Respiratory trac infection [ICD-11: CA45]; [21]
• Target: Staphylococcus 30S ribosomal subunit (Stap-coc pbp2); F4NA87_STAAU; [1]
• Formula: C21H39N7O12
• IsoSMILES: C[C@H]1[C@@]([C@H]([C@@H](O1)O[C@@H]2[C@H]([C@@H]([C@H]([C@@H]([C@H]2O)O)N=C(N)N)O)N=C(N)N)O[C@H]3[C@H]([C@@H]([C@H]([C@@H](O3)CO)O)O)NC)(C=O)O
• InChI: 1S/C21H39N7O12/c1-5-21(36,4-30)16(40-17-9(26-2)13(34)10(31)6(3-29)38-17)18(37-5)39-15-8(28-20(24)25)11(32)7(27-19(22)23)12(33)14(15)35/h4-18,26,29,31-36H,3H2,1-2H3,(H4,22,23,27)(H4,24,25,28)/t5-,6-,7+,8-,9-,10-,11+,12-,13-,14+,15+,16-,17-,18-,21+/m0/s1
• InChIKey: UCSJYZPVAKXKNQ-HZYVHMACSA-N
• PubChem CID: 19649
• ChEBI ID: CHEBI:17076
• TTD Drug ID: D0N0EQ
• INTEDE ID: DR2387
• DrugBank ID: DB01082

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Cholera [ICD-11: 1A00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: AAC(6')-Ib family aminoglycoside 6'-N-acetyltransferase (AAC6IB) [22]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae PL107b; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of aac(6')-Ib lead to drug resistance.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [22]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae O26 strain AS482; 567107
• In Vitro Model: Vibrio cholerae O39 strain AS634; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of aadA1-S lead to drug resistance.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [9]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli k-12 strain TOP10; 83333
• In Vitro Model: Vibrio cholerae O1 C10488; 127906
• In Vitro Model: Vibrio cholerae O1 strain CO943; 127906
• In Vitro Model: Vibrio cholerae O139 1811/98; 45888
• In Vitro Model: Vibrio cholerae O139 2055; 45888
• In Vitro Model: Vibrio cholerae O139 AS207; 45888
• In Vitro Model: Vibrio cholerae O139 E712; 45888
• In Vitro Model: Vibrio cholerae O139 HkO139-SXTS; 45888
• In Vitro Model: Vibrio cholerae O139 strain MO10; 345072
• Experiment for Molecule Alteration: Sequencing assay
• Mechanism Description: Many recent Asian clinical Vibrio cholerae E1 Tor O1 and O139 isolates are resistant to the antibiotics sulfamethoxazole (Su), trimethoprim (Tm), chloramphenicol (Cm), and streptomycin (Sm). The corresponding resistance genes are located on large conjugative elements (SXT constins) that are integrated into prfC on the V. cholerae chromosome. The DNA sequences of the antibiotic resistance genes in the SXT constin in MO10, an O139 isolate. In SXT(MO10), these genes are clustered within a composite transposon-like structure found near the element's 5' end. The genes conferring resistance to Cm (floR), Su (sulII), and Sm (strA and strB) correspond to previously described genes, whereas the gene conferring resistance to Tm, designated dfr18, is novel.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Streptomycin phosphotransferase (STRB) [9]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli k-12 strain TOP10; 83333
• In Vitro Model: Vibrio cholerae O1 C10488; 127906
• In Vitro Model: Vibrio cholerae O1 strain CO943; 127906
• In Vitro Model: Vibrio cholerae O139 1811/98; 45888
• In Vitro Model: Vibrio cholerae O139 2055; 45888
• In Vitro Model: Vibrio cholerae O139 AS207; 45888
• In Vitro Model: Vibrio cholerae O139 E712; 45888
• In Vitro Model: Vibrio cholerae O139 HkO139-SXTS; 45888
• In Vitro Model: Vibrio cholerae O139 strain MO10; 345072
• Experiment for Molecule Alteration: Sequencing assay
• Mechanism Description: Many recent Asian clinical Vibrio cholerae E1 Tor O1 and O139 isolates are resistant to the antibiotics sulfamethoxazole (Su), trimethoprim (Tm), chloramphenicol (Cm), and streptomycin (Sm). The corresponding resistance genes are located on large conjugative elements (SXT constins) that are integrated into prfC on the V. cholerae chromosome. The DNA sequences of the antibiotic resistance genes in the SXT constin in MO10, an O139 isolate. In SXT(MO10), these genes are clustered within a composite transposon-like structure found near the element's 5' end. The genes conferring resistance to Cm (floR), Su (sulII), and Sm (strA and strB) correspond to previously described genes, whereas the gene conferring resistance to Tm, designated dfr18, is novel.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydrofolate reductase (DHFR) [22]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae O62 strain AS438; 666
• In Vitro Model: Vibrio cholerae PG149a; 666
• In Vitro Model: Vibrio cholerae PG262(b); 666
• In Vitro Model: Vibrio cholerae PG9; 666
• In Vitro Model: Vibrio cholerae PG95; 666
• In Vitro Model: Vibrio cholerae PL1; 666
• In Vitro Model: Vibrio cholerae PL61; 666
• In Vitro Model: Vibrio cholerae PL78/6; 666
• In Vitro Model: Vibrio cholerae PL91; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of dfrA1 lead to drug resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [22]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae PG170; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of dfrA15 lead to drug resistance.

Bacterial infection [ICD-11: 1A00-1C4Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Streptomycin 3''-adenylyltransferase (AADA27) [23]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter lwoffii VS15; 28090
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Pseudomonas sp. Tik3; 761262
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The genes aadA or ant(3")-1 encode streptomycin 3"-adenylyltransferase that mediates combined resistance to streptomycin and spectinomycin through an adenylation modification. aadA27 is a functionally active gene conferring high level of resistance to streptomycin and spectinomycin in the native A. lwoffii strain as well as in Escherichia coli.

Key Molecule: Aminoglycoside acetyltransferase (AAC) [24]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio fluvialis H-08942; 676
• Experiment for Molecule Alteration: PCR; DNA sequencing assay; Southern hybridization assay; Cloning and expression assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aac(3)-Id is a new type of aminoglycoside acetyltransferase gene which causes drug resistance.

Key Molecule: AADA9 protein (AADA9) [8]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Corynebacterium glutamicum infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum ATCC 13032; 196627
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: AadA9 is a novel aminoglycoside adenyltransferase gene cassette which lead to drug resistance.

Key Molecule: Aminoglycoside 6-adenylyltransferase (A6AD) [15], [16]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Bacillus subtilis strain 168; 1423
• In Vitro Model: Bacillus subtilis strain 169; 1423
• In Vitro Model: Bacillus subtilis strain 170; 1423
• In Vitro Model: Bacillus subtilis strain 171; 1423
• In Vitro Model: Bacillus subtilis strain 172; 1423
• In Vitro Model: Bacillus subtilis strain 173; 1423
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: B. subtilis 168 produce s a chromosomally encoded aminoglycoside 6-adenylyltransferase, AAD(6),which inactivates S M by adenylation at the C-6 position of streptomycin.

Key Molecule: Aminoglycoside 6-adenylyltransferase AadS (AAADS) [25]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bacteroides fragilis strain IB131; 817
• In Vitro Model: Bacteroides ovatus strains IB106; 28116
• In Vitro Model: Bacteroides ovatus strains IB136; 28116
• In Vitro Model: Bacteroides uniformis strain IB128; 820
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The aadS-encoded peptide displayed significant homology to Gram-positive streptomycin-dependent adenyltransferases, and enzymatic analysis confirmed the production of this activity.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: TolC family outer membrane protein (TOLC) [26]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AYE WT; 509173
• In Vitro Model: Acinetobacter baumannii AYE detaabuO; 509173
• In Vitro Model: Acinetobacter baumannii AYE detaabuO Omega abuO; 509173
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: AbuO, an OMP, confers broad-spectrum antimicrobial resistance via active efflux in A. baumannii.

Escherichia coli intestinal infection [ICD-11: 1A03]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [27]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli Co227; 562
• In Vitro Model: Escherichia coli Co228; 562
• In Vitro Model: Escherichia coli Co232; 562
• In Vitro Model: Escherichia coli Co354; 562
• Experiment for Molecule Alteration: PCR; PCR-restriction fragment length polymorphism analysis; Sequencing assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Multiple-antibiotic-resistant phenotype is associated with gene mutation and mar locus regulation.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [27]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli Co227; 562
• In Vitro Model: Escherichia coli Co228; 562
• In Vitro Model: Escherichia coli Co232; 562
• In Vitro Model: Escherichia coli Co354; 562
• Experiment for Molecule Alteration: PCR; PCR-restriction fragment length polymorphism analysis; Sequencing assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Multiple-antibiotic-resistant phenotype is associated with gene mutation and mar locus regulation.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Acetylpolyamine amidohydrolase (APAH) [10]

• Molecule Alteration: Expression; Acquired
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The aphA15 gene is the first example of an aph-like gene carried on a mobile gene cassette, and its product exhibits close similarity to the APH(3')-IIa aminoglycoside phosphotransferase encoded by Tn5 (36% amino acid identity) and to an APH(3')-IIb enzyme from Pseudomonas aeruginosa (38% amino acid identity). Expression of the cloned aphA15 gene in Escherichia coli reduced the susceptibility to kanamycin and neomycin as well as (slightly) to amikacin, netilmicin, and streptomycin.

Key Molecule: Aminoglycoside adenylyltransferase (AAD5) [18]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain 9516014-1; 562
• In Vitro Model: Escherichia coli strain k-12 J62-2; 83333
• In Vitro Model: Salmonella enterica serotype Typhimurium DT104 no. 9720921; 90371
• Experiment for Molecule Alteration: Sequencing with the QIAquick purification kit assay
• Experiment for Drug Resistance: Sensititre system assay
• Mechanism Description: The aadA genes are the only characterized genes that encode both streptomycin and spectinomycin resistance, and many of these genes are found as gene cassettes.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [28]

• Molecule Alteration: Expression; Acquired
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain k12; 83333
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The nucleotide sequence of 1400 bp from R-plasmid R538-1 containing the streptomycin/spectinomycin adenyltransferase gene (aadA) was determined, and the location of the aadA gene was identified by a combination of insertion and deletion mutants. Its gene product, aminoglycoside 3"-adenylyltransferase (AAD(3")(9), has a Mr of 31,600.

Salmonellosis [ICD-11: 1A09]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [11]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enterica serovar typhimurium strain; 90371
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: Besides the genes present in the multidrug-resistant Salmonella serovar Typhimurium strains, other genes related to antibiotic resistance were described in Salmonella serovar Typhimurium or other closely related species. Tetracycline resistance could also be encoded by tetA, tetB, tetC or aadA21.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Catalase isozyme A/Tetracycline efflux MFS transporter/Dihydropteroate synthase (CATA1/TETB/SUL) [29]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella agona 231; 58095
• Experiment for Molecule Alteration: PCR screening assay
• Experiment for Drug Resistance: Disc diffusion assay
• Mechanism Description: The multiresistance plasmid from S. Agona strain 231 carried the chloramphenicol resistance gene catA1 coding for a type A chloramphenicol acetyltransferase and the resistance gene tet(B) coding for a tetracycline/minocycline exporter. This plasmid also harboured the streptomycin resistance gene strA coding for an aminoglycoside phosphotransferase and the sulphonamide resistance gene sul1 which represents part of the 3' conserved segment of class 1 integrons.

Non-tuberculous mycobacteria infection [ICD-11: 1B21]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Lincomycin resistance efflux pump (LMRS) [7]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Superficial skin infection by Staphylococcus aureus infection [ICD-11: 1B21.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• In Vitro Model: Staphylococcus aureus OM505; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: LmrS is a multidrug efflux pump of the major facilitator superfamily from staphylococcus aureus.

Gram-negative bacterial infection [ICD-11: 1B74-1G40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MipA/OmpV family protein (MIPA) [19]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gram-negative bacterial infection [ICD-11: 1B74-1G40]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli k-12 BW25113; 679895
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: OM proteins, a unique OM component of Gram-negative bacteria, constitute a barrier against large hydrophilic and lipophilic molecules and therefore play an important role in stress responses to drugs, osmotic pressure and acids.MipA is a novel OM protein related to antibiotic resistance.

Pasteurellosis [ICD-11: 1B99]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [20]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Pasteurella multocida infection [ICD-11: 1B99.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Pasteurella multocida 36950; 1075089
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The analysis of one representative P. multocida isolate identified an 82 kb integrative and conjugative element (ICE) integrated into the chromosomal DNA. This ICE, designated ICEPmu1, harboured 11 resistance genes, which confer resistance to streptomycin/spectinomycin (aadA25), streptomycin (strA and strB), gentamicin (aadB), kanamycin/neomycin (aphA1), tetracycline [tetR-tet(H)], chloramphenicol/florfenicol (floR), sulphonamides (sul2), tilmicosin/clindamycin [erm(42)] or tilmicosin/tulathromycin [msr(E)-mph(E)].

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [20]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Pasteurella multocida infection [ICD-11: 1B99.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Pasteurella multocida 36950; 1075089
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The analysis of one representative P. multocida isolate identified an 82 kb integrative and conjugative element (ICE) integrated into the chromosomal DNA. This ICE, designated ICEPmu1, harboured 11 resistance genes, which confer resistance to streptomycin/spectinomycin (aadA25), streptomycin (strA and strB), gentamicin (aadB), kanamycin/neomycin (aphA1), tetracycline [tetR-tet(H)], chloramphenicol/florfenicol (floR), sulphonamides (sul2), tilmicosin/clindamycin [erm(42)] or tilmicosin/tulathromycin [msr(E)-mph(E)].

Key Molecule: Streptomycin phosphotransferase (STRB) [20]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Pasteurella multocida infection [ICD-11: 1B99.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Pasteurella multocida 36950; 1075089
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The analysis of one representative P. multocida isolate identified an 82 kb integrative and conjugative element (ICE) integrated into the chromosomal DNA. This ICE, designated ICEPmu1, harboured 11 resistance genes, which confer resistance to streptomycin/spectinomycin (aadA25), streptomycin (strA and strB), gentamicin (aadB), kanamycin/neomycin (aphA1), tetracycline [tetR-tet(H)], chloramphenicol/florfenicol (floR), sulphonamides (sul2), tilmicosin/clindamycin [erm(42)] or tilmicosin/tulathromycin [msr(E)-mph(E)].

Key Molecule: Aminoglycoside (AADB) [20]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Pasteurella multocida infection [ICD-11: 1B99.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Pasteurella multocida 36950; 1075089
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The analysis of one representative P. multocida isolate identified an 82 kb integrative and conjugative element (ICE) integrated into the chromosomal DNA. This ICE, designated ICEPmu1, harboured 11 resistance genes, which confer resistance to streptomycin/spectinomycin (aadA25), streptomycin (strA and strB), gentamicin (aadB), kanamycin/neomycin (aphA1), tetracycline [tetR-tet(H)], chloramphenicol/florfenicol (floR), sulphonamides (sul2), tilmicosin/clindamycin [erm(42)] or tilmicosin/tulathromycin [msr(E)-mph(E)].

Campylobacteriosis [ICD-11: 1C40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Streptomycin aminoglycoside adenylyltransferase ant(6)-Ib (SA6IB) [17]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Campylobacter fetus infection [ICD-11: 1C40.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli S17-1 Lambdapir; 1227813
• Experiment for Molecule Alteration: Illumina/Solexa sequencing assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: The 286-amino-acid streptomycin resistance determinant, ANT(6)-Ib, belongs to a family of aminoglycoside nucleotidyltransferases. The resistance phenotypes were demonstrated by gene inactivation and expression.

Actinomycetoma [ICD-11: 1C43]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Streptomycin 3''-kinase (APHE) [14]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Streptomyces griseus infection [ICD-11: 1C43.7]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptomyces griseus strain ATCC 12475; 1911
• Mechanism Description: The aminoglycoside phosphotransferases are prokaryotic antibiotic resistance proteins that achieve inactivation of their antibiotic substrates by phosphorylation. To assist in our structure/function investigations of this group of kinases a gene encoding a streptomycin phosphotransferase (aphE) was cloned from the chromosomal DNA of the streptomycin producing Streptomyces griseus ATCC 12475 by the polymerase chain reaction (PCR).

Toxic shock syndrome [ICD-11: 1C45]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Lincomycin resistance efflux pump (LMRS) [7]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• In Vitro Model: Staphylococcus aureus OM505; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: LmrS is a multidrug efflux pump of the major facilitator superfamily from staphylococcus aureus.

HIV associated with tuberculosis [ICD-11: 1C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 30S ribosomal protein S12 (RPSL) [1], [2], [3]

• Molecule Alteration: Mutantion; p.K43R+p.K88Q+p.K88R
• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis strain; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Mycobacterium tuberculosis is associated either with missense mutations in the rpsL gene, which encodes ribosomal protein S12, or with base substitutions at position 904 in the 16S rRNA.Streptomycin resistant isolates harbored mutations in rpsL (codons k43R, k88Q, k88R) and rrs (nucleotide A514C).

ICD-11: Circulatory system diseases

Infective endocarditis [ICD-11: BB40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Lincomycin resistance efflux pump (LMRS) [7]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• In Vitro Model: Staphylococcus aureus OM505; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: LmrS is a multidrug efflux pump of the major facilitator superfamily from staphylococcus aureus.

ICD-12: Respiratory system diseases

Serious necrotizing pneumonia [ICD-11: CA43]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Lincomycin resistance efflux pump (LMRS) [7]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• In Vitro Model: Staphylococcus aureus OM505; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: LmrS is a multidrug efflux pump of the major facilitator superfamily from staphylococcus aureus.

Respiratory trac infection [ICD-11: CA45]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [21]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Pasteurella multocida infection [ICD-11: 1B99.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli JM109 cells; 562
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AadA14 is the fifth reading frame in pCCk647 coded for a (3")(9) adenylyltransferase of 261 amino acids. The emergence of aada14 leads to drug resistance.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [21]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Mannheimia haemolytica infection [ICD-11: CA45.3]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli JM109 cells; 562
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AadA14 is the fifth reading frame in pCCk647 coded for a (3")(9) adenylyltransferase of 261 amino acids. The emergence of aada14 leads to drug resistance.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [21]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Histophilus somni infection [ICD-11: CA45.2]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli JM109 cells; 562
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AadA14 is the fifth reading frame in pCCk647 coded for a (3")(9) adenylyltransferase of 261 amino acids. The emergence of aada14 leads to drug resistance.

ICD-21: Symptoms/clinical signs/unclassified clinical findings

Bacteremia [ICD-11: MA15]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Lincomycin resistance efflux pump (LMRS) [7]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• In Vitro Model: Staphylococcus aureus OM505; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: LmrS is a multidrug efflux pump of the major facilitator superfamily from staphylococcus aureus.

ICD-22: Injury/poisoning/certain external causes consequences

Surgical wound infection [ICD-11: NE81]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Lincomycin resistance efflux pump (LMRS) [7]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• In Vitro Model: Staphylococcus aureus OM505; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: LmrS is a multidrug efflux pump of the major facilitator superfamily from staphylococcus aureus.

References

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