Drug Information

Drug (ID: DG00290) and It's Reported Resistant Information

• Name: Josamycin
• Synonyms: Josacine; Josamicina; Josamycine; Josamycinum; EN 141; Kitasamycin A3; Leucomycin A3; Turimycin A5; Antibiotic yl-704 A3; Iosalide (TN); Josacine (TN); Josalid (TN); Josamicina [INN-Spanish]; Josamina (TN); Josamy (TN); Josamycin (TN); Josamycine [INN-French]; Josamycinum [INN-Latin]; Wilprafen (TN); Yl-704 A3; Josamycin [USAN:INN:JAN]; Josamycin (JP15/USAN/INN); Dro-2H-pyran-3-yl 3-methylbutanoate; Leucomycin V, 3-acetate 4B-(3-methylbutanoate); Leucomycin V, 3-acetate 4(sup B)-(3-methylbutanoate); Leucomycin V,3-acetate 4(sup beta)-(3-methylbutanoate)
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Bacterial meningitis [ICD-11: 1D02]; [2]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Actinomycetoma [ICD-11: 1C43]; [1]
• Target: Bacterial 50S ribosomal RNA (Bact 50S rRNA); NOUNIPROTAC; [1]
• Formula: C42H69NO15
• IsoSMILES: C[C@@H]1C/C=C/C=C/[C@@H]([C@@H](C[C@@H]([C@@H]([C@H]([C@@H](CC(=O)O1)OC(=O)C)OC)O[C@H]2[C@@H]([C@H]([C@@H]([C@H](O2)C)O[C@H]3C[C@@]([C@H]([C@@H](O3)C)OC(=O)CC(C)C)(C)O)N(C)C)O)CC=O)C)O
• InChI: 1S/C42H69NO15/c1-23(2)19-32(47)56-40-27(6)53-34(22-42(40,8)50)57-37-26(5)54-41(36(49)35(37)43(9)10)58-38-29(17-18-44)20-24(3)30(46)16-14-12-13-15-25(4)52-33(48)21-31(39(38)51-11)55-28(7)45/h12-14,16,18,23-27,29-31,34-41,46,49-50H,15,17,19-22H2,1-11H3/b13-12+,16-14+/t24-,25-,26-,27+,29+,30+,31-,34+,35-,36-,37-,38+,39+,40+,41+,42-/m1/s1
• InChIKey: XJSFLOJWULLJQS-NGVXBBESSA-N
• PubChem CID: 5282165
• ChEBI ID: CHEBI:31739
• TTD Drug ID: D0X1WJ
• DrugBank ID: DB01321

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Actinomycetoma [ICD-11: 1C43]

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
• 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.

Bacterial meningitis [ICD-11: 1D02]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23s rRNA [2]

• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• Molecule Alteration: Missense mutation; A2058G
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: M. pneumoniae M129; 2093
• Experiment for Molecule Alteration: GeneSeq assay; PCR
• Experiment for Drug Resistance: Antimicrobial susceptibility assay
• Mechanism Description: Since the secondary treatment choice for pediatric patients is very limited, we decided to look for potential new treatment strategies in macrolide drugs and investigate possible new mechanisms of resistance. We performed an in vitro selection of mutants resistant to five macrolides (erythromycin, roxithromycin, azithromycin, josamycin, and midecamycin) by inducing the parent M. pneumoniae strain M129 with increasing concentrations of the drugs. The evolving cultures in every passage were tested for their antimicrobial susceptibilities to eight drugs and mutations known to be associated with macrolide resistance by PCR and sequencing. The final selected mutants were also analyzed by whole-genome sequencing. Results showed that roxithromycin is the drug that most easily induces resistance (at 0.25 mg/L, with two passages, 23 days), while with midecamycin it is most difficult (at 5.12 mg/L, with seven passages, 87 days). Point mutations C2617A/T, A2063G, or A2064C in domain V of 23S rRNA were detected in mutants resistant to the 14- and 15-membered macrolides, while A2067G/C was selected for the 16-membered macrolides. Single amino acid changes (G72R, G72V) in ribosomal protein L4 emerged during the induction by midecamycin. Genome sequencing identified sequence variations in dnaK, rpoC, glpK, MPN449, and in one of the hsdS (MPN365) genes in the mutants. Mutants induced by the 14- or 15-membered macrolides were resistant to all macrolides, while those induced by the 16-membered macrolides (midecamycin and josamycin) remained susceptible to the 14- and 15-membered macrolides. In summary, these data demonstrated that midecamycin is less potent in inducing resistance than other macrolides, and the induced resistance is restrained to the 16-membered macrolides, suggesting a potential benefit of using midecamycin as a first treatment choice if the strain is susceptible.

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: Novel mechanisms of macrolide resistance revealed by in vitro selection and genome analysis in Mycoplasma pneumoniae. Front Cell Infect Microbiol. 2023 May 22;13:1186017.