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Mechanisms of Resistance

Multiple Mutations Modulate the Function of Dihydrofolate Reductase in Trimethoprim-ResistantStreptococcus pneumoniae

Jeffrey P. Maskell, Armine M. Sefton, Lucinda M. C. Hall
Jeffrey P. Maskell
Department of Medical Microbiology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London E1 2AD, United Kingdom
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Armine M. Sefton
Department of Medical Microbiology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London E1 2AD, United Kingdom
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Lucinda M. C. Hall
Department of Medical Microbiology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London E1 2AD, United Kingdom
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DOI: 10.1128/AAC.45.4.1104-1108.2001
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Tables

  • Table 1.

    Sources and characteristics of trimethoprim-resistant and -susceptible S. pneumoniae isolates

    IsolateSourceaSerotypebMIC (mg/liter)
    SulfamethoxazoleTrimethoprim
    Pn94/720cCSF23F512256
    Pn93/1293dBlood culture6B512256
    Pn93/1802eBlood culture9V256256
    P48UnknownND1,024256
    R12SputumND256512
    Pn93/1791Blood culture19F164
    Pn93/917CSF9V328
    Pn93/908CSF14324
    Pn94/258Blood culture23F324
    CP1015—644
    ATCC 49619—644
    • ↵a CSF, cerebrospinal fluid.

    • ↵b ND, not done; —, nonencapsulated.

    • ↵c “Spanish” 23F multiresistant clone.

    • ↵d “Spanish” 6B multiresistant clone.

    • ↵e “French/Spanish” 9V multiresistant clone.

  • Table 2.

    Amino acid differences in DHFR sequences of trimethoprim-resistant and -susceptible isolates

    IsolateAmino acid at positiona:MIC (mg/liter)
    14*1620*265360*70*74*7881*838691*92*94*100*111120133135*147149*164
    ATCC 49619EVEHMKPIAQVVQDEIPHELFAK4
    CP1015—L—————————————————————4
    Pn93/1791———————————I——————K————4
    Pn93/917——D——————————A——A——————8
    Pn93/908——D——————————A——A——————4
    Pn94/258—————————————A——A——————4
    Pn93/720D—D———SL—H——HADL———FSTE256
    Pn93/1293——DY——S—TY———SDL———FSS—256
    Pn93/1802——DYIQS—T————A—L—Q—FST—256
    P48——D———S——HI——ADL—Q—FST—256
    R12——DYIQS—T————A—L—Q—FST—512
    • ↵a *, positions at which amino acids are altered in all trimethoprim-resistant isolates reported by Hartman et al. (37th ICAAC), Adrian and Klugman (1), Pikis et al. (15), and the present study; —, amino acid is the same as in ATCC 49619.

  • Table 3.

    Amino acid sequence changes and DHFR characteristics of selected CP1015 transformants

    IsolateAmino acid at positiona:MIC (mg/liter)IC50(μM)Km(μM)bSpecificity constantc
    1416202653*6070747881919294100*†120135147149DHFNADPH
    ATCC 49619V40.053.9 (0.83)17.8 (4.4)0.024
    CP1015ELEHMKPIAQQDEIHLFA40.093.1 (0.48)18.2 (3.2)0.014
    720/T1DVDSLHHADLFST5122.99.2 (3.3)30.7 (7.9)0.09
    720/T2VDSLHHADL2561.412.6 (3.3)21.9 (5.2)0.04
    1802/T1VDYIQSTALQFST51213.714.3 (2.3)29.0 (4.4)0.026
    1802/T2VDYIQSTAL51210.124.1 (8.6)52.7 (23.7)0.007
    R12/T1TALQFST2562.115.2 (2.8)20.3 (4.7)0.016
    R12/T2AL1284.227.7 (9.7)35.1 (11.4)0.0063
    • ↵a *, trimethoprim binding site in the DHFR of E. coli K-12; †, NADPH binding site in the DHFR ofE. coli K-12 (as reported by Dale et al. [4, 5]).

    • ↵b Values in parentheses are standard errors.

    • ↵c Vmax/Km(μM).

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Multiple Mutations Modulate the Function of Dihydrofolate Reductase in Trimethoprim-ResistantStreptococcus pneumoniae
Jeffrey P. Maskell, Armine M. Sefton, Lucinda M. C. Hall
Antimicrobial Agents and Chemotherapy Apr 2001, 45 (4) 1104-1108; DOI: 10.1128/AAC.45.4.1104-1108.2001

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Multiple Mutations Modulate the Function of Dihydrofolate Reductase in Trimethoprim-ResistantStreptococcus pneumoniae
Jeffrey P. Maskell, Armine M. Sefton, Lucinda M. C. Hall
Antimicrobial Agents and Chemotherapy Apr 2001, 45 (4) 1104-1108; DOI: 10.1128/AAC.45.4.1104-1108.2001
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KEYWORDS

Anti-Infective Agents, Urinary
mutation
Streptococcus pneumoniae
Tetrahydrofolate Dehydrogenase
trimethoprim

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