Disease Information

General Information of the Disease (ID: DIS00030)

• Name: Actinomycetoma
• ICD: ICD-11: 1C43

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Drug

Approved Drug(s) 13 drug(s) in total

Carbomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: srmA open reading frame gimA (GIMA) [1]

• Resistant Disease: Streptomyces ambbyaciens infection [ICD-11: 1C43.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Carbomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain S17.1; 1227813
• In Vitro Model: Micrococcus luteus strain Cgr; 1270
• In Vitro Model: Micrococcus luteus strain DSM1790; 1270
• In Vitro Model: Streptomyces ambofaciens strain ATCC 23877; 278992
• In Vitro Model: Streptomyces ambofaciens strain OS41.99; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS41.99NP; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS81; 1954
• In Vitro Model: Streptomyces lividans strain OS456; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Observation of growth inhibition zones assay
• Mechanism Description: With UDP-[14C]glucose as the cofactor, crude S30 extracts from OS456(pOS41.90) were tested on various macrolides. Among those, chalcomycin was the most active substrate. Methymycin, tylosin, pikromycin, and rosaramicin were four of the best substrates. Oleandomycin, josamycin, and carbomycin were glycosylated to a lesser extent. Macrolides that were found to be as poor substrates of GimA as lankamycin were erythromycin and angolamycin. Spiramycin was also a very poor substrate.

Chloramphenicol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Chloramphenicol 3-O phosphotransferase (CH3OP) [2]

• Resistant Disease: Streptomyces venezuelae infection [ICD-11: 1C43.10]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli JM101; 562
• In Vitro Model: Streptomyces lividans strain M252; 1916
• Experiment for Molecule Alteration: Dideoxy chain-termination method assay
• Experiment for Drug Resistance: Measuring the diameters of inhibition zones around the disks assay
• Mechanism Description: The product of the ORF from S. venezuelae as an enzymic effector of Cm resistance in the producing organism by 3'-O-phosphorylation. We suggest the trivial name chloramphenicol 3'-O-phosphotransferase for the enzyme.

Erythromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Oleandomycin glycosyltransferase oleD (OLED) [3]

• Resistant Disease: Streptomyces infection [ICD-11: 1C43.6]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Erythromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• Experiment for Molecule Alteration: Linked enzyme activity assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Glycosylation of macrolide antibiotics confers host cell immunity from endogenous and exogenous agents. The Streptomyces antibioticus glycosyltransferases, OleD, diverse macrolides including erythromycin.

Key Molecule: srmA open reading frame gimA (GIMA) [1]

• Resistant Disease: Streptomyces ambbyaciens infection [ICD-11: 1C43.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Erythromycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain S17.1; 1227813
• In Vitro Model: Micrococcus luteus strain Cgr; 1270
• In Vitro Model: Micrococcus luteus strain DSM1790; 1270
• In Vitro Model: Streptomyces ambofaciens strain ATCC 23877; 278992
• In Vitro Model: Streptomyces ambofaciens strain OS41.99; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS41.99NP; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS81; 1954
• In Vitro Model: Streptomyces lividans strain OS456; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Observation of growth inhibition zones assay
• Mechanism Description: With UDP-[14C]glucose as the cofactor, crude S30 extracts from OS456(pOS41.90) were tested on various macrolides. Among those, chalcomycin was the most active substrate. Methymycin, tylosin, pikromycin, and rosaramicin were four of the best substrates. Oleandomycin, josamycin, and carbomycin were glycosylated to a lesser extent. Macrolides that were found to be as poor substrates of GimA as lankamycin were erythromycin and angolamycin. Spiramycin was also a very poor substrate.

Framycetin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(3)-acetyltransferase VIII (A3AC8) [4]

• Resistant Disease: Streptomyces fradiae infection [ICD-11: 1C43.5]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Framycetin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Micromonospora chalcea strain 69-683; 1874
• In Vitro Model: Streptomyces fradiae strain ATCC 10745; 1319510
• Experiment for Molecule Alteration: Southern-blot hybridization assay
• Mechanism Description: In the case of S. fradiae ATCC10745, a Nm producer, an O-phosphotransferase (APH) encoded by the aphA-5 gene and an N-acetyltransferase (AAC) have been identified. The aphA-5 gene is thought to be part of a biosynthetic cluster; the sac gene is not closely linked to aph; however, high-level Nm resistance in Streptomyces requires expression of both uph and sac.

Key Molecule: Aminoglycoside N(3)-acetyltransferase IX (A3AC9) [4]

• Resistant Disease: Streptomyces fradiae infection [ICD-11: 1C43.5]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Framycetin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Micromonospora chalcea strain 69-683; 1874
• In Vitro Model: Streptomyces fradiae strain ATCC 10745; 1319510
• Experiment for Molecule Alteration: Southern-blot hybridization assay
• Mechanism Description: In the case of S. fradiae ATCC10745, a Nm producer, an O-phosphotransferase (APH) encoded by the aphA-5 gene and an N-acetyltransferase (AAC) have been identified. The aphA-5 gene is thought to be part of a biosynthetic cluster; the sac gene is not closely linked to aph; however, high-level Nm resistance in Streptomyces requires expression of both uph and sac.

Kanamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(3)-acetyltransferase (A3AC) [5]

• Resistant Disease: Streptomyces griseus infection [ICD-11: 1C43.7]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Kanamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptomyces griseus strain SS-1198; 1911
• In Vitro Model: Streptomyces lividans strain Tk21; 1916
• In Vitro Model: Streptomyces lividans strain pIJ702; 1916
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Maximum growth allowance concentrations assay
• Mechanism Description: We determined the molecular basis for the enhanced expression of the aac(3)-Xa gene encoding an aminoglycoside 3-N-acetyltransferase in Streptomyces griseus. A C-->T substitution was identified at the putative promoter of the mutant gene. RNA analyses demonstrated that the substitution caused a marked increase in the production of the gene-specific transcripts. Therefore, it seemed very likely that the aac(3)-Xa gene was activated by the substitution resulting in the emergence of a stronger promoter.

Key Molecule: Aminoglycoside N(3)-acetyltransferase (A3AC) [5]

• Resistant Disease: Streptomyces lividans infection [ICD-11: 1C43.8]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Kanamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptomyces griseus strain SS-1198; 1911
• In Vitro Model: Streptomyces lividans strain Tk21; 1916
• In Vitro Model: Streptomyces lividans strain pIJ702; 1916
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Maximum growth allowance concentrations assay
• Mechanism Description: After the insertion of these fragments into pIJ702 with all possible combinations, the hybrid genes were tested for their ability to confer km resistance to S. lividans Tk21. A high level (1,000 ug/ml) of km resistance was obtained only with genes containing the 0.5-kb BglII-BamHI fragment derived from the mutant gene. By contrast, genes containing the 0.5-kb fragment from the wild-type gene conferred resistance to km at concentrations as low as 50 ug/ml.

Macrolides

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: srmA open reading frame gimA (GIMA) [1]

• Resistant Disease: Streptomyces ambbyaciens infection [ICD-11: 1C43.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Macrolides
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain S17.1; 1227813
• In Vitro Model: Micrococcus luteus strain Cgr; 1270
• In Vitro Model: Micrococcus luteus strain DSM1790; 1270
• In Vitro Model: Streptomyces ambofaciens strain ATCC 23877; 278992
• In Vitro Model: Streptomyces ambofaciens strain OS41.99; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS41.99NP; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS81; 1954
• In Vitro Model: Streptomyces lividans strain OS456; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Observation of growth inhibition zones assay
• Mechanism Description: With UDP-[14C]glucose as the cofactor, crude S30 extracts from OS456(pOS41.90) were tested on various macrolides. Among those, chalcomycin was the most active substrate. Methymycin, tylosin, pikromycin, and rosaramicin were four of the best substrates. Oleandomycin, josamycin, and carbomycin were glycosylated to a lesser extent. Macrolides that were found to be as poor substrates of GimA as lankamycin were erythromycin and angolamycin. Spiramycin was also a very poor substrate.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Tylosin resistance ATP-binding protein TlrC (TLRC) [6]

• Resistant Disease: Streptomyces fradiae infection [ICD-11: 1C43.5]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Macrolides
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptomyces fradiae strain; 1906
• In Vitro Model: Treptomyces fradia strain; 1906
• Experiment for Molecule Alteration: Northern blotting analysis
• Mechanism Description: A tylosin(Ty)-producing strain of Streptomyces fradiae contains at least three genes, tlrA, tlrB, tlrC, specifying resistance to Ty (TyR).

Key Molecule: Tylosin resistance ATP-binding protein TlrC (TLRC) [6]

• Resistant Disease: Streptomyces fradiae infection [ICD-11: 1C43.5]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Macrolides
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptomyces fradiae strain; 1906
• In Vitro Model: Treptomyces fradia strain; 1906
• Experiment for Molecule Alteration: Northern blotting analysis
• Mechanism Description: The product of the tlrA gene is an rRNA methylase responsible for dimethylation of a specific A residue in S. fradiae 23s rRNA (Zalacain and Cundliffe, 1989). In contrast, the Ty-inducible resistance encoded by tlrB or tlrC appears to be specific for Ty and each imparts lower levels of TyR than does tlrA.

Matromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Oleandomycin glycosyltransferase oleI (OLEL) [3]

• Resistant Disease: Streptomyces infection [ICD-11: 1C43.6]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Matromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• Experiment for Molecule Alteration: Linked enzyme activity assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Glycosylation of macrolide antibiotics confers host cell immunity from endogenous and exogenous agents. The Streptomyces antibioticus glycosyltransferases, OleI, glycosylate and inactivate oleandomycin.

Key Molecule: srmA open reading frame gimA (GIMA) [1]

• Resistant Disease: Streptomyces ambbyaciens infection [ICD-11: 1C43.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Matromycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain S17.1; 1227813
• In Vitro Model: Micrococcus luteus strain Cgr; 1270
• In Vitro Model: Micrococcus luteus strain DSM1790; 1270
• In Vitro Model: Streptomyces ambofaciens strain ATCC 23877; 278992
• In Vitro Model: Streptomyces ambofaciens strain OS41.99; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS41.99NP; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS81; 1954
• In Vitro Model: Streptomyces lividans strain OS456; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Observation of growth inhibition zones assay
• Mechanism Description: With UDP-[14C]glucose as the cofactor, crude S30 extracts from OS456(pOS41.90) were tested on various macrolides. Among those, chalcomycin was the most active substrate. Methymycin, tylosin, pikromycin, and rosaramicin were four of the best substrates. Oleandomycin, josamycin, and carbomycin were glycosylated to a lesser extent. Macrolides that were found to be as poor substrates of GimA as lankamycin were erythromycin and angolamycin. Spiramycin was also a very poor substrate.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding protein (ABP) [7]

• Resistant Disease: Streptomyces antibioticus infection [ICD-11: 1C43.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Matromycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptomyces antibioticus strain; 1890
• Experiment for Molecule Alteration: Fluorescence measurements assay
• Mechanism Description: The OleB protein ofStreptomyces antibioticus, oleandomycin (OM) producer, constitutes an ATP-binding cassette transporter containing two nucleotide-binding domains and is involved in OM resistance and its secretion in this producer strain.

Key Molecule: ATP-binding protein (ABP) [8]

• Resistant Disease: Streptomyces antibioticus infection [ICD-11: 1C43.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Matromycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptomyces albus J1074; 457425
• In Vitro Model: Streptomyces lividans strain Tk21; 1916
• In Vitro Model: Escherichia coli strain ED8767; 562
• In Vitro Model: Escherichia coli strain TGI; 83333
• In Vitro Model: Streptomyces antibioticu strain ATCC 11891; 1890
• Experiment for Molecule Alteration: DNA hybridizations assay
• Mechanism Description: Three different DNA fragments of an oleandomycin producer, Streptomyces antibioticus, conferring oleandomycin resistance were cloned in plasmid pIJ702 and expressed in Streptomyces lividans and in Streptomyces albus. These oleandomycin resistance determinants were designated as oleA (pOR400), oleB (pOR501) and oleC (pOR800). The oleC (orf4) gene product had a hydrophilic profile and showed important similarity with proteins containing typical ATP-binding domains characteristic of the ABC-transporter superfamily and involved in membrane transport and, particularly, with several genes conferring resistance to various macrolide antibiotics and anticancer drugs.

Ribostamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

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

• Resistant Disease: Streptomyces lividans infection [ICD-11: 1C43.8]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ribostamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli strain JM103; 83333
• In Vitro Model: Bacillus circulans strain; 1397
• In Vitro Model: Streptomyces lividans strain 66; 1200984
• In Vitro Model: Streptomyces lividans strain M180; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Semi-quantitative phosphocellulose-paper binding assay method assay
• Mechanism Description: In attempts to express the B. circulans APH gene in Strep. lividans 66,the 2.7kb Sal1-digest insert of pCH5 was transferred to the Streptomyces vector SLP1.2 by ligating a mixture of a Sal1-digest of pCH5 (1ug) and a partial digest of SLP1.2 (0.5ug) cut at one or two sites of its three Sal1 sites. After incubation, 51 patches of drug-resistant growth were seen. This demonstrated that the ribostamycin-resistance is linked to the plasmid.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [10]

• Resistant Disease: Streptomyces ribosidificus infection [ICD-11: 1C43.14]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ribostamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptomyces lividans strain 66; 1200984
• In Vitro Model: Escherichia coli strain DH-SCY; 562
• In Vitro Model: Escherichia coli strain k-12; 83333
• In Vitro Model: Streptomyces hygroscopicus strain SF1084; 1912
• In Vitro Model: Streptomyces ribosidificus strain SF733; 80859
• Experiment for Molecule Alteration: Northern hybridization assay
• Experiment for Drug Resistance: Gradient-plate technique of Szybalski assay
• Mechanism Description: The rph gene conferring ribostamycin 3'-O-phosphorylation was isolated from a ribostamycin producer, S. ribosidifcus SF733.

Rosaramicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: srmA open reading frame gimA (GIMA) [1]

• Resistant Disease: Streptomyces ambbyaciens infection [ICD-11: 1C43.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Rosaramicin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain S17.1; 1227813
• In Vitro Model: Micrococcus luteus strain Cgr; 1270
• In Vitro Model: Micrococcus luteus strain DSM1790; 1270
• In Vitro Model: Streptomyces ambofaciens strain ATCC 23877; 278992
• In Vitro Model: Streptomyces ambofaciens strain OS41.99; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS41.99NP; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS81; 1954
• In Vitro Model: Streptomyces lividans strain OS456; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Observation of growth inhibition zones assay
• Mechanism Description: With UDP-[14C]glucose as the cofactor, crude S30 extracts from OS456(pOS41.90) were tested on various macrolides. Among those, chalcomycin was the most active substrate. Methymycin, tylosin, pikromycin, and rosaramicin were four of the best substrates. Oleandomycin, josamycin, and carbomycin were glycosylated to a lesser extent. Macrolides that were found to be as poor substrates of GimA as lankamycin were erythromycin and angolamycin. Spiramycin was also a very poor substrate.

Spiramycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: srmA open reading frame gimA (GIMA) [1]

• Resistant Disease: Streptomyces ambbyaciens infection [ICD-11: 1C43.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Spiramycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain S17.1; 1227813
• In Vitro Model: Micrococcus luteus strain Cgr; 1270
• In Vitro Model: Micrococcus luteus strain DSM1790; 1270
• In Vitro Model: Streptomyces ambofaciens strain ATCC 23877; 278992
• In Vitro Model: Streptomyces ambofaciens strain OS41.99; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS41.99NP; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS81; 1954
• In Vitro Model: Streptomyces lividans strain OS456; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Observation of growth inhibition zones assay
• Mechanism Description: With UDP-[14C]glucose as the cofactor, crude S30 extracts from OS456(pOS41.90) were tested on various macrolides. Among those, chalcomycin was the most active substrate. Methymycin, tylosin, pikromycin, and rosaramicin were four of the best substrates. Oleandomycin, josamycin, and carbomycin were glycosylated to a lesser extent. Macrolides that were found to be as poor substrates of GimA as lankamycin were erythromycin and angolamycin. Spiramycin was also a very poor substrate.

Streptomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Streptomycin 3''-kinase (APHE) [11]

• Resistant Disease: Streptomyces griseus infection [ICD-11: 1C43.7]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Streptomycin
• 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).

Tetracycline

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Oxytetracycline resistance efflux MFS transporter OtrB (OTRB) [12]

• Resistant Disease: Streptomyces rimosus infection [ICD-11: 1C43.12]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptomyces rimosus strain; 1927
• Mechanism Description: The sequence of the tetracycline resistance gene designated tet347 from the tetracycline-producing organism Streptomyces rimosus (strain PG3) predicted a protein of 347 amino acids (GenBank accession no. M20370). The tcrC gene (also called tcr3; GenBank accession no. D38215) from chlorotetracycline-producing S. aureofaciens encoded a 512-residue putative tetracycline efflux protein which, starting at residue 222, was 43% identical to the Tet347 protein.

Key Molecule: Protein tcr3 (TCR3) [13]

• Resistant Disease: Streptomyces aurebyaciens infection [ICD-11: 1C43.2]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain XLI-Blue; 562
• In Vitro Model: Streptomyces aureofaciens strain NRRL3203; 1894
• In Vitro Model: Streptomyces lividans strain Tk23; 1916
• Experiment for Molecule Alteration: Northern blotting analysis
• Mechanism Description: The analysis of the nucleotide sequence of the 2.8-kb BamHI fragment containing tcrC gene showed that the predicted tcrC gene product is a protein consisting of 512 amino acids. The deduced amino acid sequence had a high level identity with that of the self-defense gene (tet347) of Streptomyces rimosus, known to mediate oxytetracycline efflux. The tcrC gene-inactivated strains generated from strain NRRL3203 by gene replacement had a 90% decrease in the level of resistance to tetracycline and the antibiotic productivity when compared with the parental strain.

Viomycin sulfate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Viomycin phosphotransferase (VPH) [14]

• Resistant Disease: Streptomyces vinaceus infection [ICD-11: 1C43.11]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Viomycin sulfate
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Escherichia coli strain ED8767; 562
• In Vitro Model: Streptomyces lividans strain M252; 1916
• In Vitro Model: Streptomyces lividans strain 66; 1200984
• In Vitro Model: Escherichia coli strain W5445; 562
• In Vitro Model: Streptomyces lividans strain M264; 1916
• In Vitro Model: Streptomyces lividans strain M274; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: Promoter-probe plasmid vectors were used to isolate putative promoter-containing DNA fragments of three Streptomyces antibiotic resistance genes, the rRNA methylase (tsr) gene of S. azureus, the aminoglycoside phosphotransferase (aph) gene of S. fradiae, and the viomycin phosphotransferase (vph) gene of S. vinaceus.

Clinical Trial Drug(s) 2 drug(s) in total

Josamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: srmA open reading frame gimA (GIMA) [1]

• Resistant Disease: Streptomyces ambbyaciens infection [ICD-11: 1C43.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Josamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain S17.1; 1227813
• In Vitro Model: Micrococcus luteus strain Cgr; 1270
• In Vitro Model: Micrococcus luteus strain DSM1790; 1270
• In Vitro Model: Streptomyces ambofaciens strain ATCC 23877; 278992
• In Vitro Model: Streptomyces ambofaciens strain OS41.99; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS41.99NP; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS81; 1954
• In Vitro Model: Streptomyces lividans strain OS456; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Observation of growth inhibition zones assay
• Mechanism Description: With UDP-[14C]glucose as the cofactor, crude S30 extracts from OS456(pOS41.90) were tested on various macrolides. Among those, chalcomycin was the most active substrate. Methymycin, tylosin, pikromycin, and rosaramicin were four of the best substrates. Oleandomycin, josamycin, and carbomycin were glycosylated to a lesser extent. Macrolides that were found to be as poor substrates of GimA as lankamycin were erythromycin and angolamycin. Spiramycin was also a very poor substrate.

Thiostrepton

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23S rRNA (adenosine(1067)-2'-O)-methyltransferase (TSNR) [15]

• Resistant Disease: Streptomyces laurentii infection [ICD-11: 1C43.9]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Thiostrepton
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain XL-1 Blue MRF; 562
• In Vitro Model: Streptomyces laurentii strain; 39478
• In Vitro Model: Streptomyces lividans strain Tk24; 457428
• Experiment for Molecule Alteration: DNA hybridizations assay
• Mechanism Description: The Th R (tsnR) gene from SI is highly similar to the Th R and Nh R genes from Saz and Sac. Partial nt sequence analysis of the DNA flanking the Sl tsnR gene indicates that tsnR is clustered with r-protein operons. Insert-directed integration of pkCl132 within this region supports the idea that, in S1, tsnR is not clustered with genes encoding Th biosynthetic enzymes.

Key Molecule: 23S rRNA (adenosine(1067)-2'-O)-methyltransferase (TSNR) [15]

• Resistant Disease: Streptomyces lividans infection [ICD-11: 1C43.8]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Thiostrepton
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain XL-1 Blue MRF; 562
• In Vitro Model: Streptomyces laurentii strain; 39478
• In Vitro Model: Streptomyces lividans strain Tk24; 457428
• Experiment for Molecule Alteration: DNA hybridizations assay
• Mechanism Description: The Th R (tsnR) gene from SI is highly similar to the Th R and Nh R genes from Saz and Sac. Partial nt sequence analysis of the DNA flanking the Sl tsnR gene indicates that tsnR is clustered with r-protein operons. Insert-directed integration of pkCl132 within this region supports the idea that, in S1, tsnR is not clustered with genes encoding Th biosynthetic enzymes.

Key Molecule: 23S rRNA (adenosine(1067)-2'-O)-methyltransferase (TSNR) [14]

• Resistant Disease: Streptomyces azureus infection [ICD-11: 1C43.4]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Thiostrepton
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Escherichia coli strain ED8767; 562
• In Vitro Model: Streptomyces lividans strain M252; 1916
• In Vitro Model: Streptomyces lividans strain 66; 1200984
• In Vitro Model: Escherichia coli strain W5445; 562
• In Vitro Model: Streptomyces lividans strain M264; 1916
• In Vitro Model: Streptomyces lividans strain M274; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: Promoter-probe plasmid vectors were used to isolate putative promoter-containing DNA fragments of three Streptomyces antibiotic resistance genes, the rRNA methylase (tsr) gene of S. azureus, the aminoglycoside phosphotransferase (aph) gene of S. fradiae, and the viomycin phosphotransferase (vph) gene of S. vinaceus. The rRNA methylase (tsr) gene of S. azureus, which confers resistance to thiostrepton by methylation of 23S rRNA.

Discontinued Drug(s) 1 drug(s) in total

Angolamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: srmA open reading frame gimA (GIMA) [1]

• Resistant Disease: Streptomyces ambbyaciens infection [ICD-11: 1C43.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Angolamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain S17.1; 1227813
• In Vitro Model: Micrococcus luteus strain Cgr; 1270
• In Vitro Model: Micrococcus luteus strain DSM1790; 1270
• In Vitro Model: Streptomyces ambofaciens strain ATCC 23877; 278992
• In Vitro Model: Streptomyces ambofaciens strain OS41.99; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS41.99NP; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS81; 1954
• In Vitro Model: Streptomyces lividans strain OS456; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Observation of growth inhibition zones assay
• Mechanism Description: With UDP-[14C]glucose as the cofactor, crude S30 extracts from OS456(pOS41.90) were tested on various macrolides. Among those, chalcomycin was the most active substrate. Methymycin, tylosin, pikromycin, and rosaramicin were four of the best substrates. Oleandomycin, josamycin, and carbomycin were glycosylated to a lesser extent. Macrolides that were found to be as poor substrates of GimA as lankamycin were erythromycin and angolamycin. Spiramycin was also a very poor substrate.

Investigative Drug(s) 5 drug(s) in total

Chalcomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: srmA open reading frame gimA (GIMA) [1]

• Resistant Disease: Streptomyces ambbyaciens infection [ICD-11: 1C43.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chalcomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain S17.1; 1227813
• In Vitro Model: Micrococcus luteus strain Cgr; 1270
• In Vitro Model: Micrococcus luteus strain DSM1790; 1270
• In Vitro Model: Streptomyces ambofaciens strain ATCC 23877; 278992
• In Vitro Model: Streptomyces ambofaciens strain OS41.99; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS41.99NP; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS81; 1954
• In Vitro Model: Streptomyces lividans strain OS456; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Observation of growth inhibition zones assay
• Mechanism Description: With UDP-[14C]glucose as the cofactor, crude S30 extracts from OS456(pOS41.90) were tested on various macrolides. Among those, chalcomycin was the most active substrate. Methymycin, tylosin, pikromycin, and rosaramicin were four of the best substrates. Oleandomycin, josamycin, and carbomycin were glycosylated to a lesser extent. Macrolides that were found to be as poor substrates of GimA as lankamycin were erythromycin and angolamycin. Spiramycin was also a very poor substrate.

Kirromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Elongation factor Tu (TUF) [16]

• Resistant Disease: Streptomyces cinnamoneus infection [ICD-11: 1C43.3]
• Molecule Alteration: Missense mutation; p.T378A
• Resistant Drug: Kirromycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain DH5alpha; 668369
• In Vitro Model: Escherichia coli strain JM109; 83333
• In Vitro Model: Streptomyces lividans strain 1326; 1200984
• In Vitro Model: Nocardia lactamdurans strain ATCC 27382; 1913
• In Vitro Model: Streptomyces cinnamoneus strain Tu89; 53446
• In Vitro Model: Streptomyces coelicolor strain M145; 1902
• In Vitro Model: Streptomyces glaucescens strain ETH 22794; 1907
• Experiment for Molecule Alteration: Southern hybridization assay
• Mechanism Description: The antibiotic kirromycin (kr) inhibits bacterial protein synthesis by binding to elongation factor Tu (EF-Tu). Streptomyces cinnamoneus and Nocardia lactamdurans, producers of antibiotics of the kr class, are known to possess an EF-Tu resistant to kr. Thr378, was mutated to the consensus Ala and the resulting mutant protein was sensitive to kr. Interestingly, it retained some activity (30% of the control) even at high kr concentrations.

Lankamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: srmA open reading frame gimA (GIMA) [1]

• Resistant Disease: Streptomyces ambbyaciens infection [ICD-11: 1C43.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Lankamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain S17.1; 1227813
• In Vitro Model: Micrococcus luteus strain Cgr; 1270
• In Vitro Model: Micrococcus luteus strain DSM1790; 1270
• In Vitro Model: Streptomyces ambofaciens strain ATCC 23877; 278992
• In Vitro Model: Streptomyces ambofaciens strain OS41.99; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS41.99NP; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS81; 1954
• In Vitro Model: Streptomyces lividans strain OS456; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Observation of growth inhibition zones assay
• Mechanism Description: With UDP-[14C]glucose as the cofactor, crude S30 extracts from OS456(pOS41.90) were tested on various macrolides. Among those, chalcomycin was the most active substrate. Methymycin, tylosin, pikromycin, and rosaramicin were four of the best substrates. Oleandomycin, josamycin, and carbomycin were glycosylated to a lesser extent. Macrolides that were found to be as poor substrates of GimA as lankamycin were erythromycin and angolamycin. Spiramycin was also a very poor substrate.

Methymycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: srmA open reading frame gimA (GIMA) [1]

• Resistant Disease: Streptomyces ambbyaciens infection [ICD-11: 1C43.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Methymycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain S17.1; 1227813
• In Vitro Model: Micrococcus luteus strain Cgr; 1270
• In Vitro Model: Micrococcus luteus strain DSM1790; 1270
• In Vitro Model: Streptomyces ambofaciens strain ATCC 23877; 278992
• In Vitro Model: Streptomyces ambofaciens strain OS41.99; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS41.99NP; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS81; 1954
• In Vitro Model: Streptomyces lividans strain OS456; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Observation of growth inhibition zones assay
• Mechanism Description: With UDP-[14C]glucose as the cofactor, crude S30 extracts from OS456(pOS41.90) were tested on various macrolides. Among those, chalcomycin was the most active substrate. Methymycin, tylosin, pikromycin, and rosaramicin were four of the best substrates. Oleandomycin, josamycin, and carbomycin were glycosylated to a lesser extent. Macrolides that were found to be as poor substrates of GimA as lankamycin were erythromycin and angolamycin. Spiramycin was also a very poor substrate.

Streptothricin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Streptothricin acetyltransferase (STA) [17]

• Resistant Disease: Streptomyces lavendulae infection [ICD-11: 1C43.13]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Streptothricin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptomyces lividans strain Tk21; 1916
• In Vitro Model: Bacillus subtilis strain RM141; 1423
• In Vitro Model: Escherichia coli strain 5131-5; 562
• Experiment for Molecule Alteration: [a-32P] dCTP by the dideoxynucleoside triphosphate chain termination method assay
• Mechanism Description: The nucleotide sequence of the streptothricin acetyltransferase (STAT) gene from streptothricin-producing Streptomyces lavendulae predicts a 189-amino-acid protein of molecular weight 20,000, which is consistent with that determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified enzyme. By addition of promoter signals and a synthetic ribosome-binding (Shine-Dalgarno) sequence at an appropriate position upstream of the STAT translational start codon, the STAT gene confers streptothricin resistance on Escherichia coli and Bacillus subtilis.

References

• Ref 1: Characterization of a glycosyl transferase inactivating macrolides, encoded by gimA from Streptomyces ambofaciens. Antimicrob Agents Chemother. 1998 Oct;42(10):2612-9. doi: 10.1128/AAC.42.10.2612.
• Ref 2: Inactivation of chloramphenicol by O-phosphorylation. A novel resistance mechanism in Streptomyces venezuelae ISP5230, a chloramphenicol producer. J Biol Chem. 1995 Nov 10;270(45):27000-6. doi: 10.1074/jbc.270.45.27000.
• Ref 3: The crystal structure of two macrolide glycosyltransferases provides a blueprint for host cell antibiotic immunity. Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5336-41. doi: 10.1073/pnas.0607897104. Epub 2007 Mar 21.
• Ref 4: Characterisation of aminoglycoside acetyltransferase-encoding genes of neomycin-producing Micromonospora chalcea and Streptomyces fradiae. Gene. 1991 May 15;101(1):143-8. doi: 10.1016/0378-1119(91)90237-6.
• Ref 5: Identification and characterization of the point mutation which affects the transcription level of the chromosomal 3-N-acetyltransferase gene of Streptomyces griseus SS-1198. Antimicrob Agents Chemother. 2000 Feb;44(2):437-40. doi: 10.1128/AAC.44.2.437-440.2000.
• Ref 6: Homology between proteins controlling Streptomyces fradiae tylosin resistance and ATP-binding transport. Gene. 1991 Jun 15;102(1):27-32. doi: 10.1016/0378-1119(91)90533-h.
• Ref 7: Interaction between ATP, oleandomycin and the OleB ATP-binding cassette transporter of Streptomyces antibioticus involved in oleandomycin secretion. Biochem J. 1997 Jan 1;321 ( Pt 1)(Pt 1):139-44. doi: 10.1042/bj3210139.
• Ref 8: Streptomyces antibioticus contains at least three oleandomycin-resistance determinants, one of which shows similarity with proteins of the ABC-transporter superfamily. Mol Microbiol. 1993 May;8(3):571-82. doi: 10.1111/j.1365-2958.1993.tb01601.x.
• Ref 9: Sequence and interspecies transfer of an aminoglycoside phosphotransferase gene (APH) of Bacillus circulans. Self-defence mechanism in antibiotic-producing organisms. Biochem J. 1986 Jan 15;233(2):383-93. doi: 10.1042/bj2330383.
• Ref 10: Nucleotide sequence of the ribostamycin phosphotransferase gene and of its control region in Streptomyces ribosidificus. Gene. 1988 Sep 7;68(2):285-96. doi: 10.1016/0378-1119(88)90031-5.
• Ref 11: PCR cloning of a streptomycin phosphotransferase (aphE) gene from Streptomyces griseus ATCC 12475. Nucleic Acids Res. 1990 Aug 11;18(15):4615. doi: 10.1093/nar/18.15.4615.
• Ref 12: Revised sequence of OtrB (tet347) tetracycline efflux protein from Streptomyces rimosus. Antimicrob Agents Chemother. 1998 Nov;42(11):3050. doi: 10.1128/AAC.42.11.3050.
• Ref 13: A self-defense gene homologous to tetracycline effluxing gene essential for antibiotic production in Streptomyces aureofaciens. Biosci Biotechnol Biochem. 1995 Oct;59(10):1835-41. doi: 10.1271/bbb.59.1835.
• Ref 14: Nucleotide sequences encoding and promoting expression of three antibiotic resistance genes indigenous to Streptomyces. Mol Gen Genet. 1985;199(1):26-36. doi: 10.1007/BF00327505.
• Ref 15: The thiostrepton-resistance-encoding gene in Streptomyces laurentii is located within a cluster of ribosomal protein operons. Gene. 1995 Oct 16;164(1):137-42. doi: 10.1016/0378-1119(95)00442-9.
• Ref 16: Natural kirromycin resistance of elongation factor Tu from the kirrothricin producer Streptomyces cinnamoneus. Microbiology (Reading). 1997 Feb;143 ( Pt 2):617-624. doi: 10.1099/00221287-143-2-617.
• Ref 17: Nucleotide sequence of the streptothricin acetyltransferase gene from Streptomyces lavendulae and its expression in heterologous hosts. J Bacteriol. 1987 May;169(5):1929-37. doi: 10.1128/jb.169.5.1929-1937.1987.