Disease Information

General Information of the Disease (ID: DIS00036)

• Name: Bacterial meningitis
• ICD: ICD-11: 1D02

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

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 9 drug(s) in total

Colistin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Multifunctional fusion protein (LPXA) [1], [2]

• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• Resistant Drug: Colistin
• Molecule Alteration: Frameshift mutation; c.90del
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii ATCC 19606; 575584
• In Vitro Model: Acinetobacter baumannii FADDI008; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [1], [2]

• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• Resistant Drug: Colistin
• Molecule Alteration: Missense mutation; p.H159D
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AL1844; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [1], [2]

• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• Resistant Drug: Colistin
• Molecule Alteration: Missense mutation; c.700C>T
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AL1845; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [1], [2]

• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• Resistant Drug: Colistin
• Molecule Alteration: Missense mutation; p.G68D
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AL1846; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [1], [2]

• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• Resistant Drug: Colistin
• Molecule Alteration: Frameshift mutation; c.391_421del
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii ATCC 19606; 575584
• In Vitro Model: Acinetobacter baumannii FADDI008; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [1], [2]

• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• Resistant Drug: Colistin
• Molecule Alteration: Missense mutation; p.Q72K
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AL1848; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [1], [2]

• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• Resistant Drug: Colistin
• Molecule Alteration: Frameshift mutation; c.76_78del
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii ATCC 19606; 575584
• In Vitro Model: Acinetobacter baumannii FADDI008; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [1], [2]

• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• Resistant Drug: Colistin
• Molecule Alteration: Frameshift mutation; c.364_809del
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii ATCC 19606; 575584
• In Vitro Model: Acinetobacter baumannii FADDI008; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Erythromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23S rRNA (cytidine-2'-O)-methyltransferase TlyA (TLYA) [3]

• Resistant Disease: Mycoplasma pneumoniae infection [ICD-11: 1D01.3]
• Resistant Drug: Erythromycin
• Molecule Alteration: Missense mutation; p.A2063G+p.A2064G+p.A2617G
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycoplasma pneumoniae strain; 2014
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: It has been confirmed that drug resistance to macrolide antibiotics of MP is mainly related to the mutation of Gene 23SrRNA in Area V, most commonly in the mutation of A2063G and followed by A2064G and A2617G. Rarely, mutation of ribosomal protein L4 or L22 may induce drug resistance to macrolide antibiotics.

Key Molecule: 23s rRNA [4]

• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• Resistant Drug: Erythromycin
• Molecule Alteration: Missense mutation; c.421C>A (rs2231142)
• 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.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MsrC (MSRC) [5]

• Resistant Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Resistant Drug: Erythromycin
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Enterococcus faecium TX2465; 1352
• In Vitro Model: Escherichia coli TX1330; 668369
• In Vitro Model: Escherichia coli TX2046; 668369
• In Vitro Model: Escherichia coli TX2597; 668369
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: The complete sequence (1,479 nucleotides) of msrC, part of which was recently reported by others using a different strain, was determined. This gene was found in 233 of 233 isolates of Enterococcus faecium but in none of 265 other enterococci. Disruption of msrC was associated with a two- to eightfold decrease in MICs of erythromycin azithromycin, tylosin, and quinupristin, suggesting that it may explain in part the apparent greater intrinsic resistance to macrolides of isolates of E. faecium relative to many streptococci. This endogenous, species-specific gene of E. faecium is 53% identical to msr(A), suggesting that it may be a remote progenitor of the acquired macrolide resistance gene found in some isolates of staphylococci.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MsrC (MSRC) [5]

• Sensitive Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Sensitive Drug: Erythromycin
• Molecule Alteration: Truncated mutantion; Disruption (nt 1251 to 1879)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Enterococcus faecium TX2465; 1352
• In Vitro Model: Escherichia coli TX1330; 668369
• In Vitro Model: Escherichia coli TX2046; 668369
• In Vitro Model: Escherichia coli TX2597; 668369
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: Disruption of msrC was associated with a two- to eightfold decrease in MICs of erythromycin azithromycin, tylosin, and quinupristin, suggesting that it may explain in part the apparent greater intrinsic resistance to macrolides of isolates of E. faecium relative to many streptococci.

Macrolides

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MsrC (MSRC) [5]

• Resistant Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Resistant Drug: Macrolides
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Enterococcus faecium TX2465; 1352
• In Vitro Model: Escherichia coli TX1330; 668369
• In Vitro Model: Escherichia coli TX2046; 668369
• In Vitro Model: Escherichia coli TX2597; 668369
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: The complete sequence (1,479 nucleotides) of msrC, part of which was recently reported by others using a different strain, was determined. This gene was found in 233 of 233 isolates of Enterococcus faecium but in none of 265 other enterococci. Disruption of msrC was associated with a two- to eightfold decrease in MICs of erythromycin azithromycin, tylosin, and quinupristin, suggesting that it may explain in part the apparent greater intrinsic resistance to macrolides of isolates of E. faecium relative to many streptococci. This endogenous, species-specific gene of E. faecium is 53% identical to msr(A), suggesting that it may be a remote progenitor of the acquired macrolide resistance gene found in some isolates of staphylococci.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MsrC (MSRC) [5]

• Sensitive Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Sensitive Drug: Macrolides
• Molecule Alteration: Truncated mutantion; Disruption (nt 1251 to 1879)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Enterococcus faecium TX2465; 1352
• In Vitro Model: Escherichia coli TX1330; 668369
• In Vitro Model: Escherichia coli TX2046; 668369
• In Vitro Model: Escherichia coli TX2597; 668369
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: Disruption of msrC was associated with a two- to eightfold decrease in MICs of erythromycin azithromycin, tylosin, and quinupristin, suggesting that it may explain in part the apparent greater intrinsic resistance to macrolides of isolates of E. faecium relative to many streptococci.

Plazomicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside phosphotransferase (APH) [6]

• Resistant Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Resistant Drug: Plazomicin
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecium SF11770; 1352
• In Vitro Model: Escherichia coli kHE5-2a; 562
• In Vitro Model: Escherichia coli strain DH10b(pMW119); 316385
• Experiment for Molecule Alteration: PCR
• Mechanism Description: High-level gentamicin resistance (MIC >= 500 ug/ml) in enterococci is predominantly mediated by aac(6')-Ie-aph(2")-Ia, which encodes the bifunctional aminoglycoside-modifying enzyme AAC(6')-APH(2"). Found less commonly is aph(2")-Id, another gene recently reported to be associated with high-level gentamicin resistance in enterococci.

Quinupristin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MsrC (MSRC) [5]

• Resistant Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Resistant Drug: Quinupristin
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Enterococcus faecium TX2465; 1352
• In Vitro Model: Escherichia coli TX1330; 668369
• In Vitro Model: Escherichia coli TX2046; 668369
• In Vitro Model: Escherichia coli TX2597; 668369
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: The complete sequence (1,479 nucleotides) of msrC, part of which was recently reported by others using a different strain, was determined. This gene was found in 233 of 233 isolates of Enterococcus faecium but in none of 265 other enterococci. Disruption of msrC was associated with a two- to eightfold decrease in MICs of erythromycin azithromycin, tylosin, and quinupristin, suggesting that it may explain in part the apparent greater intrinsic resistance to macrolides of isolates of E. faecium relative to many streptococci. This endogenous, species-specific gene of E. faecium is 53% identical to msr(A), suggesting that it may be a remote progenitor of the acquired macrolide resistance gene found in some isolates of staphylococci.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MsrC (MSRC) [5]

• Sensitive Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Sensitive Drug: Quinupristin
• Molecule Alteration: Truncated mutantion; Disruption (nt 1251 to 1879)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Enterococcus faecium TX2465; 1352
• In Vitro Model: Escherichia coli TX1330; 668369
• In Vitro Model: Escherichia coli TX2046; 668369
• In Vitro Model: Escherichia coli TX2597; 668369
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: Disruption of msrC was associated with a two- to eightfold decrease in MICs of erythromycin azithromycin, tylosin, and quinupristin, suggesting that it may explain in part the apparent greater intrinsic resistance to macrolides of isolates of E. faecium relative to many streptococci.

Roxithromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23s rRNA [4]

• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• Resistant Drug: Roxithromycin
• Molecule Alteration: Missense mutation; V600E
• 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.

Teicoplanin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: D-alanine ligase (vanD5) [7]

• Resistant Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Resistant Drug: Teicoplanin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecium isolates; 1352
• Experiment for Molecule Alteration: Whole-genome sequencing assay
• Experiment for Drug Resistance: Broth dilution assay
• Mechanism Description: Glycopeptide (vancomycin and teicoplanin) resistance is attributed to the acquisition of vancomycin resistance (van) genes. Nine van genes that encode a D-Ala:D-Lac or D-Ala:D-Ser ligase (vanA, vanB, vanC, vanD, vanE, vanG, vanL, vanM and vanN) have been identified in Enterococcus spp. d-Alanyl:d-lactate (d-Ala:d-Lac) and d-alanyl:d-serine ligases are key enzymes in vancomycin resistance of Gram-positive cocci. They catalyze a critical step in the synthesis of modified peptidoglycan precursors that are low binding affinity targets for vancomycin.

Tetracycline

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Tetracycline resistance protein TetU (TETU) [8]

• Resistant Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Resistant Drug: Tetracycline
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Enterococcus faecalis strain JH2-2; 1320322
• In Vitro Model: Enterococcus faecium strain CH2; 1352
• Experiment for Molecule Alteration: DNA Hybridization assay
• Experiment for Drug Resistance: Tube dilution method assay
• Mechanism Description: PkQ10, a 1.9-kb plasmid carrying a novel Tc resistance determinant, was isolated from one of the isolates. The nucleotide sequence of this plasmid revealed an open reading frame corresponding to an 11.8-kDa protein and containing 105 amino acid residues. There was some limited similarity between this protein andtet(M),tet(O),tet(Q),tet(S),tetB(P), andotr(A), which overlapped, but did not include, the consensus GTP-binding sequences. The low-level, Tc-resistant determinant of pkQ10, namedtet(U), does not appear to correspond to any other known Tc resistance determinant.

Zithromax

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23s rRNA [4]

• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• Resistant Drug: Zithromax
• Molecule Alteration: Missense mutation; A2059G
• 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.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MsrC (MSRC) [5]

• Resistant Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Resistant Drug: Zithromax
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Enterococcus faecium TX2465; 1352
• In Vitro Model: Escherichia coli TX1330; 668369
• In Vitro Model: Escherichia coli TX2046; 668369
• In Vitro Model: Escherichia coli TX2597; 668369
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: The complete sequence (1,479 nucleotides) of msrC, part of which was recently reported by others using a different strain, was determined. This gene was found in 233 of 233 isolates of Enterococcus faecium but in none of 265 other enterococci. Disruption of msrC was associated with a two- to eightfold decrease in MICs of erythromycin azithromycin, tylosin, and quinupristin, suggesting that it may explain in part the apparent greater intrinsic resistance to macrolides of isolates of E. faecium relative to many streptococci. This endogenous, species-specific gene of E. faecium is 53% identical to msr(A), suggesting that it may be a remote progenitor of the acquired macrolide resistance gene found in some isolates of staphylococci.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MsrC (MSRC) [5]

• Sensitive Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Sensitive Drug: Zithromax
• Molecule Alteration: Truncated mutantion; Disruption (nt 1251 to 1879)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Enterococcus faecium TX2465; 1352
• In Vitro Model: Escherichia coli TX1330; 668369
• In Vitro Model: Escherichia coli TX2046; 668369
• In Vitro Model: Escherichia coli TX2597; 668369
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: Disruption of msrC was associated with a two- to eightfold decrease in MICs of erythromycin azithromycin, tylosin, and quinupristin, suggesting that it may explain in part the apparent greater intrinsic resistance to macrolides of isolates of E. faecium relative to many streptococci.

Clinical Trial Drug(s) 1 drug(s) in total

Josamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23s rRNA [4]

• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• Resistant Drug: Josamycin
• 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.

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

Midecamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 50S ribosomal protein L4 (RplD) [4]

• Resistant Disease: Acinetobacter meningitis [ICD-11: 1D01.1]
• Resistant Drug: Midecamycin
• Molecule Alteration: Missense mutation; G214A; G215T
• 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

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• Ref 2: Biological cost of different mechanisms of colistin resistance and their impact on virulence in Acinetobacter baumannii. Antimicrob Agents Chemother. 2014;58(1):518-26. doi: 10.1128/AAC.01597-13. Epub 2013 Nov 4.
• Ref 3: Serological Analysis and Drug Resistance of Chlamydia pneumoniae and Mycoplasma pneumoniae in 4500 Healthy Subjects in Shenzhen, China .Biomed Res Int. 2017;2017:3120138. doi: 10.1155/2017/3120138. Epub 2017 Sep 19. 10.1155/2017/3120138
• Ref 4: 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.
• Ref 5: Disruption of an Enterococcus faecium species-specific gene, a homologue of acquired macrolide resistance genes of staphylococci, is associated with an increase in macrolide susceptibility. Antimicrob Agents Chemother. 2001 Jan;45(1):263-6. doi: 10.1128/AAC.45.1.263-266.2001.
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• Ref 7: Emergence of vancomycin- and teicoplanin-resistant Enterococcus faecium via vanD5-harbouring large genomic island .J Antimicrob Chemother. 2020 Sep 1;75(9):2411-2415. doi: 10.1093/jac/dkaa220. 10.1093/jac/dkaa220
• Ref 8: A novel tetracycline-resistant determinant, tet(U), is encoded on the plasmid pKq10 in Enterococcus faecium. Plasmid. 1996 Mar;35(2):71-80. doi: 10.1006/plas.1996.0009.