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      Single nucleotide polymorphisms in genes encoding penicillin-binding proteins in β-lactamase-negative ampicillin-resistant Haemophilus influenzae in Japan

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          Abstract

          Objective

          β-Lactamase-negative ampicillin-resistant Haemophilus influenzae is a common opportunistic pathogen of hospital- and community-acquired infections, harboring multiple single nucleotide polymorphisms in the ftsI gene, which codes for penicillin-binding protein-3. The objectives of this study were to perform comprehensive genetic analyses of whole regions of the penicillin-binding proteins in H. influenzae and to identify additional single nucleotide polymorphisms related to antibiotic resistance, especially to ampicillin and other cephalosporins.

          Results

          In this genome analysis of the ftsI gene in 27 strains of H. influenzae, 10 of 23 (43.5%) specimens of group III genotype β-lactamase-negative ampicillin-resistant H. influenzae were paradoxically classified as ampicillin-sensitive phenotypes. Unfortunately, we could not identify any novel mutations that were significantly associated with ampicillin minimum inhibitory concentrations in other regions of the penicillin-binding proteins, and we reconfirmed that susceptibility to β-lactam antibiotics was mainly defined by previously reported SNPs in the ftsI gene. We should also consider detailed changes in expression that lead to antibiotic resistance in the future because the acquisition of resistance to antimicrobials can be predicted by the expression levels of a small number of genes.

          Electronic supplementary material

          The online version of this article (10.1186/s13104-018-3169-0) contains supplementary material, which is available to authorized users.

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          Most cited references27

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          Antimicrobial resistance in Haemophilus influenzae.

          Haemophilus influenzae is a major community-acquired pathogen causing significant morbidity and mortality worldwide. Meningitis and bacteremia due to type b strains occur in areas where the protein-conjugated type b vaccine is not in use, whereas nontypeable strains are major causes of otitis media, sinusitis, acute exacerbations of chronic bronchitis, and pneumonia. Antibiotic resistance in this organism is more diverse and widespread than is commonly appreciated. Intrinsic efflux resistance mechanisms limit the activity of the macrolides, azalides, and ketolides. beta-Lactamase production is highly prevalent worldwide and is associated with resistance to ampicillin and amoxicillin. Strains with alterations in penicillin binding proteins, particularly PBP3 (beta-lactamase negative ampicillin resistant and beta-lactamase positive amoxicillin-clavulanate resistant), are increasing in prevalence, particularly in Japan, with increasing resistance to ampicillin, amoxicillin, amoxicillin-clavulanate, and many cephalosporins, limiting the efficacy of expanded-spectrum cephalosporins against meningitis and of many oral cephalosporins against other diseases. Most strains remain susceptible to the carbapenems, which are not affected by penicillin binding protein changes, and the quinolones. The activity of many oral agents is limited by pharmacokinetics achieved with administration by this route, and the susceptibility of isolates based on pharmacokinetic and pharmacodynamic parameters is reviewed.
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              Association of amino acid substitutions in penicillin-binding protein 3 with beta-lactam resistance in beta-lactamase-negative ampicillin-resistant Haemophilus influenzae.

              The affinity of [(3)H]benzylpenicillin for penicillin-binding protein (PBP) 3A was reduced in 25 clinical isolates of beta-lactamase-negative ampicillin (AMP)-resistant (BLNAR) Haemophilus influenzae for which the AMP MIC was > or =1.0 microg/ml. The affinities of PBP 3B and PBP 4 were also reduced in some strains. The sequences of the ftsI gene encoding the transpeptidase domain of PBP 3A and/or PBP 3B and of the dacB gene encoding PBP 4 were determined for these strains and compared to those of AMP-susceptible Rd strains. The BLNAR strains were classified into three groups on the basis of deduced amino acid substitutions in the ftsI gene, which is thought to be involved in septal peptidoglycan synthesis. His-517, near the conserved Lys-Thr-Gly (KTG) motif, was substituted for Arg-517 in group I strains (n = 9), and Lys-526 was substituted for Asn-526 in group II strains (n = 12). In group III strains (n = 4), three residues (Met-377, Ser-385, and Leu-389), positioned near the conserved Ser-Ser-Asn (SSN) motif, were replaced with Ile, Thr, and Phe, respectively, in addition to the replacement with Lys-526. The MICs of cephem antibiotics with relatively high affinities for PBP 3A and PBP 3B were higher than those of AMP and meropenem for group III strains. The MICs of beta-lactams for H. influenzae transformants into which the ftsI gene from BLNAR strains was introduced were as high as those for the donors, and PBP 3A and PBP 3B showed decreased affinities for beta-lactams. There was no clear relationship between 7-bp deletions in the dacB gene and AMP susceptibility. Even though mutations in another gene(s) may be involved in beta-lactam resistance, these data indicate that mutations in the ftsI gene are the most important for development of resistance to beta-lactams in BLNAR strains.
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                Author and article information

                Contributors
                k_misawa28@ndmc.ac.jp
                tarumoto@saitama-med.ac.jp
                tamshin007@gmail.com
                nagumomoritika@yahoo.co.jp
                hamamoto@ndmc.ac.jp
                ayuki@ndmc.ac.jp
                yukouzaki@gmail.com
                k_imai@saitama-med.ac.jp
                luckyruntuwene@edu.k.u-tokyo.ac.jp
                desfier@gmail.com
                takmu@saitama-med.ac.jp
                maesaki@saitama-med.ac.jp
                ysuzuki@k.u-tokyo.ac.jp
                kawana59@ndmc.ac.jp
                +81-49-276-1166 , t_maeda@saitama-med.ac.jp
                Journal
                BMC Res Notes
                BMC Res Notes
                BMC Research Notes
                BioMed Central (London )
                1756-0500
                20 January 2018
                20 January 2018
                2018
                : 11
                : 53
                Affiliations
                [1 ]ISNI 0000 0004 0374 0880, GRID grid.416614.0, Department of Infectious Diseases and Pulmonary Medicine, , National Defense Medical College, ; Saitama, Japan
                [2 ]ISNI 0000 0001 2216 2631, GRID grid.410802.f, Department of Infectious Disease and Infection Control, , Saitama Medical University, ; Saitama, Japan
                [3 ]ISNI 0000 0001 2216 2631, GRID grid.410802.f, Center for Clinical Infectious Diseases and Research, , Saitama Medical University, ; Saitama, Japan
                [4 ]ISNI 0000 0004 0374 0880, GRID grid.416614.0, Department of Pediatrics, , National Defense Medical College, ; Saitama, Japan
                [5 ]GRID grid.416620.7, Department of Laboratory Medicine, , National Defense Medical College Hospital, ; Saitama, Japan
                [6 ]ISNI 0000 0001 2151 536X, GRID grid.26999.3d, Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences, , The University of Tokyo, ; Chiba, Japan
                [7 ]ISNI 0000 0001 2216 2631, GRID grid.410802.f, Department of Microbiology, , Saitama Medical University, ; 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495 Japan
                Author information
                http://orcid.org/0000-0003-0912-4643
                Article
                3169
                10.1186/s13104-018-3169-0
                5775570
                29352811
                6718117c-f3a2-4f43-a57b-9a2660bed3b1
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 28 November 2017
                : 12 January 2018
                Categories
                Research Note
                Custom metadata
                © The Author(s) 2018

                Medicine
                haemophilus influenzae,β-lactamase-negative ampicillin-resistant (blnar),penicillin binding protein,snp

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