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Mechanisms of Resistance

Carbapenem-Nonsusceptible Haemophilus influenzae with Penicillin-Binding Protein 3 Containing an Amino Acid Insertion

Kazuki Kitaoka, Kouji Kimura, Hiromitsu Kitanaka, Hirotsugu Banno, Wanchun Jin, Jun-ichi Wachino, Yoshichika Arakawa
Kazuki Kitaoka
aDepartment of Bacteriology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
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Kouji Kimura
aDepartment of Bacteriology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
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Hiromitsu Kitanaka
aDepartment of Bacteriology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
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Hirotsugu Banno
aDepartment of Bacteriology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
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Wanchun Jin
aDepartment of Bacteriology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
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Jun-ichi Wachino
aDepartment of Bacteriology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
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Yoshichika Arakawa
aDepartment of Bacteriology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
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DOI: 10.1128/AAC.00671-18
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    FIG 1

    Deduced amino acid sequence of PBP3 from H. influenzae NUBL1772 compared to that of strain Rd. Dashes represent identical amino acids. Boxes highlight the three conserved motifs of the active site, specifically, Ser327-Thr-Val-Lys, Ser379-Ser-Asn, and Lys512-Thr-Gly. NUBL1772 was found to have S385T and L389F alterations. The number of amino acids in PBP3 from NUBL1772 with the V525_N526insM insertion was altered and is described in parentheses. The number of amino acids was restored in PBP3 from NUBL1772 with the T591del deletion.

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  • TABLE 1

    Characterization of seven H. influenzae isolates with reduced carbapenem susceptibility

    IsolateaRegion of sourceBiotypePatient informationMLSTbPBP3 groupcMIC (μg/ml)
    AgeSexSourceAmpicillinMeropenemDoripenemImipenemBiapenem
    NUBL970KanagawaII5MNose1763II20.060.2544
    NUBL1767IbaragiII0FNose57III+80.12448
    NUBL1771KanagawaV1MNose1764III+81448
    NUBL1772KanagawaII1MNose5716141616
    NUBL1775SaitamaII7FVagina1765III+21448
    NUBL1777NaganoV7MNose1766III+160.120.4216
    NUBL2814ChibaII5MNose1683II20.25148
    • ↵a All isolates were nontypeable and β-lactamase negative.

    • ↵b MLST, multilocus sequence type.

    • ↵c PBP3 group according to amino acid mutations: II, N526K; III+, S385T, L389F, and N526K. NUBL1772 was not categorized and possessed a new insertion mutation.

  • TABLE 2

    MICs for H. influenzae NUBL1772

    AntimicrobialMIC (μg/ml)
    RdNUBL1772
    Ampicillin0.2516
    Ampicillin-sulbactam0.2516
    Amoxicillin0.532
    Amoxicillin-clavulanic acid0.532
    Cefotaxime0.061
    Ceftriaxone≤0.030.25
    Cefepime≤0.252
    Piperacillin-tazobactam≤0.03≤0.03
    Aztreonam0.064
    Meropenem0.031
    Doripenem0.064
    Imipenem0.516
    Biapenem0.516
    Clarithromycin816
    Ciprofloxacin0.0150.03
    Levofloxacin0.0150.03
  • TABLE 3

    MICs for Rd recombinants carrying ftsI genes related to NUBL1772

    Strain or isolateaMIC (μg/ml)
    AmpicillinMeropenemDoripenemImipenemBiapenem
    Rd0.250.030.060.50.5
    NUBL177216141616
    Rd (NUBL1772 ftsI)80.5248
    Rd (Rd ftsI V525_N526insM)0.250.030.060.50.5
    Rd (NUBL1772 ftsI M526del)20.120.512
    • ↵a Rd recombinants contained the corresponding ftsI genes.

  • TABLE 4

    Binding of Bocillin FL and β-lactams to recombinant PBP3 proteins

    AntimicrobialIC50 (μg/ml) ± SDP value
    RdNUBL1772
    Ampicillin0.14 ± 0.035.13 ± 1.480.028
    Meropenem0.10 ± 0.020.15 ± 0.030.049
    Doripenem0.12 ± 0.050.73 ± 0.330.035
    Imipenem0.20 ± 0.153.22 ± 0.590.001
    Biapenem0.25 ± 0.085.86 ± 2.580.020
  • TABLE 5

    Transcription of acrB and efflux pump activity in H. influenzae NUBL1772 compared to that in strain Rd

    Strain or isolateRelative mRNA level of acrBP valueInitial velocity (fluorescence intensity/min) of ethidium bromide accumulationP value
    Rd1.11 ± 0.650.0381.63 ± 0.320.026
    NUBL17724.80 ± 1.980.89 ± 0.18

Additional Files

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      FIG S1 to S3, Table S1

      PDF, 7.1M

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Carbapenem-Nonsusceptible Haemophilus influenzae with Penicillin-Binding Protein 3 Containing an Amino Acid Insertion
Kazuki Kitaoka, Kouji Kimura, Hiromitsu Kitanaka, Hirotsugu Banno, Wanchun Jin, Jun-ichi Wachino, Yoshichika Arakawa
Antimicrobial Agents and Chemotherapy Jul 2018, 62 (8) e00671-18; DOI: 10.1128/AAC.00671-18

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Carbapenem-Nonsusceptible Haemophilus influenzae with Penicillin-Binding Protein 3 Containing an Amino Acid Insertion
Kazuki Kitaoka, Kouji Kimura, Hiromitsu Kitanaka, Hirotsugu Banno, Wanchun Jin, Jun-ichi Wachino, Yoshichika Arakawa
Antimicrobial Agents and Chemotherapy Jul 2018, 62 (8) e00671-18; DOI: 10.1128/AAC.00671-18
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KEYWORDS

Haemophilus influenzae
carbapenems
penicillin-binding proteins

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