Skip to main content
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems
  • Log in
  • My alerts
  • My Cart

Main menu

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About AAC
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • AAC Podcast
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems

User menu

  • Log in
  • My alerts
  • My Cart

Search

  • Advanced search
Antimicrobial Agents and Chemotherapy
publisher-logosite-logo

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About AAC
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • AAC Podcast
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
Mechanisms of Resistance

Impact of Inducible blaDHA-1 on Susceptibility of Klebsiella pneumoniae Clinical Isolates to LYS228 and Identification of Chromosomal mpl and ampD Mutations Mediating Upregulation of Plasmid-Borne blaDHA-1 Expression

Adriana K. Jones, Srijan Ranjitkar, Sara Lopez, Cindy Li, Johanne Blais, Folkert Reck, Charles R. Dean
Adriana K. Jones
aNovartis Institutes for BioMedical Research, Emeryville, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Srijan Ranjitkar
aNovartis Institutes for BioMedical Research, Emeryville, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sara Lopez
aNovartis Institutes for BioMedical Research, Emeryville, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cindy Li
aNovartis Institutes for BioMedical Research, Emeryville, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Johanne Blais
aNovartis Institutes for BioMedical Research, Emeryville, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Folkert Reck
aNovartis Institutes for BioMedical Research, Emeryville, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Charles R. Dean
aNovartis Institutes for BioMedical Research, Emeryville, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Charles R. Dean
DOI: 10.1128/AAC.01202-18
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

ABSTRACT

Twenty-three Klebsiella pneumoniae (blaDHA-1) clinical isolates exhibited a range of susceptibilities to LYS228, with MICs of ≥8 μg/ml for 9 of these. Mutants with decreased susceptibility to LYS228 and upregulated expression of blaDHA-1 were selected from representative isolates. These had mutations in the chromosomal peptidoglycan recycling gene mpl or ampD. Preexisting mpl mutations were also found in some of the clinical isolates examined, and these had strongly upregulated expression of blaDHA-1.

TEXT

Resistance to β-lactams often results from the expression of ever-evolving serine β-lactamase enzymes (SBLs) that degrade penicillins, cephalosporins, monobactams, and, in some cases, carbapenems (1). Carbapenem-resistant Enterobacteriaceae (CRE) are increasingly regarded as a public health issue (2, 3). β-Lactamase inhibitors (BLIs) counter the effect of SBLs, but metallo-β-lactamases (MBLs) such as New Delhi metallo-β-lactamase-1 (NDM-1), usually expressed together with SBLs, have emerged in Klebsiella pneumoniae and Escherichia coli (4). No inhibitors of MBLs are currently available clinically (5). The monobactam aztreonam (ATM) is stable to MBLs (6, 7) but not all SBLs. To address this, the combination of ATM with the β-lactamase inhibitor avibactam (AVI) is currently in clinical trials (ClinicalTrials registration no. NCT01689207).

We designed the monobactam LYS228, now in phase II clinical trials (ClinicalTrials registration no. NCT03354754), that is stable to both MBLs and SBLs (8). Accordingly, the MIC90 of LYS228 was 1 μg/ml against 271 Enterobacteriaceae clinical isolates, including those expressing a variety of β-lactamases (9). The MIC90 of LYS228 was 1 μg/ml against the 81 K. pneumoniae isolates included in that panel (9). Four of the 81 were annotated as having the class C β-lactamase blaDHA-1. Of these, one was found to have a truncation of the blaDHA-1 gene (data not shown). Of the other three, two were susceptible to LYS228 (NB29263 and NB29289, MIC of 0.125 to 0.5) (Table 1), but one was less susceptible (NB29293, mode MIC of 4 μg/ml) (Table 1). K. pneumoniae lacks a chromosomal ampC but can acquire class C genes (e.g., blaDHA-1) on large plasmids. Isolates with plasmid-borne blaDHA-1 have been reported in several geographic locations (10–24). Plasmid-borne blaDHA-1 likely originated from the chromosome of Morganella morganii and carries with it the associated ampR gene, making it inducible (25, 26). Inducible blaDHA-1 itself may not significantly affect susceptibility to many β-lactams, but combined with other mechanisms, such as porin defects (e.g., OmpK35 and/or OmpK36 in K. pneumoniae), it can become more important in some isolates (27, 28). These factors can complicate susceptibility testing for β-lactams, and a lack of robust methodology for identifying these isolates may result in underestimating their prevalence (19, 29–31). To explore if the variable impact of blaDHA-1 on susceptibility extended to LYS228, we expanded our panel to 23 K. pneumoniae clinical isolates, all having blaDHA-1 (among other enzymes), and determined if this panel trended toward decreased LYS228 susceptibility. The isolates originated in the United States (n = 1), Europe (n = 5), the Middle East (n = 3), and the Asia-Pacific (n = 13). The presence of the ampR-blaDHA-1 region was confirmed for all isolates by PCR and sequencing, although strain NB29381 had a C-to-A mutation 37 bp upstream of blaDHA-1 and NB29390 had an A-to-T mutation 74 bp upstream of blaDHA-1. A range of susceptibilities to LYS228 was observed (0.125 to >64 μg/ml) (Table 1), but the LYS228 MIC was ≥8 μg/ml for 9 of the strains. Therefore, although some isolates were susceptible to LYS228, the panel was overall significantly less susceptible than the set of K. pneumoniae isolates that were not selected based on the presence of blaDHA-1 (9). We partially characterized two strains from this panel that had different susceptibilities to LYS228. K. pneumoniae NB29293 susceptibility was variable, with MICs ranging from 2 to 16 μg/ml, consistent with inducibility of blaDHA-1 (mode MIC, 4 μg/ml) (Table 1). Addition of avibactam (4 μg/ml) improved the LYS228 MIC to 0.25 μg/ml (Table 1). An intact ompK35 porin gene could not be amplified by PCR, and the ompK36 porin gene encoded multiple alterations to the porin protein relative to the reference strain ATCC 43816 (32 and data not shown). These defects may be additive with the effect of the inducible DHA-1, as suggested in previous reports. A second isolate, NB29289, was consistently more susceptible to LYS228 than NB29293 (MIC of 0.125 μg/ml) (Table 1). In contrast to strain NB29293, the genes encoding OmpK35 and OmpK36 only had silent mutations compared to reference strain ATCC 43816 (32). This may explain in part why NB29289 is more sensitive to LYS228 than NB29293, but this remains to be confirmed.

View this table:
  • View inline
  • View popup
TABLE 1

Antibiotic susceptibilities of K. pneumoniae clinical isolates harboring blaDHAa

Consistent with DHA-1 affecting susceptibility to LYS228, mutants with constitutive upregulation of blaDHA-1 could be selected from strain NB29293 in vitro at a frequency of approximately 10−6 by plating cells on LB agar containing 32 μg/ml of LYS228 (8× the mode MIC). Mutant susceptibility was shifted at least 32-fold (MIC of >64 μg/ml). LYS228 activity was restored by the addition of 4 μg/ml avibactam, confirming involvement of a β-lactamase (NB29293-CDK0022) (Table 1). Genome sequencing of NB29293-CDK0022 using previously described methodology (33) revealed a premature stop codon (encoding W247*) in the chromosomal murein-peptide-ligase gene mpl, which was also present in several other mutants. An NB29293 mutant recovered from a time-kill regrowth experiment, conducted as previously described (9) (NB29293-CDK0021; Table 1), harbored a mutation in mpl encoding D31N. These mutants were constitutively upregulated for expression of blaDHA-1 (Fig. 1). Mutants were also selected from the more sensitive strain NB29289 on agar containing 1 μg/ml LYS228. Of six mutants tested, four had a 1-bp deletion (frameshift) at position 45 and one had a 1-bp deletion at position 275 of mpl. The MIC of LYS228 increased to 8 and 32 μg/ml for these mutants (NB29289-CDK0033 and CDK0034) (Table 1), and again LYS228 susceptibility was restored by the addition of avibactam (Table 1). It should be noted that no mpl mutations were isolated from several non-blaDHA-1 K. pneumoniae isolates during single-step selections described in an accompanying report (33), strengthening the association of mpl mutations with blaDHA-1. Mpl is UDP-N-acetylmuramate:L-alanyl-γ-d-glutamyl-meso-diaminopimelate ligase, involved in peptidoglycan recycling (34, 35), and its mutational loss may induce expression of blaDHA-1 via changes in peptidoglycan intermediates sensed by the plasmid-encoded AmpR regulator. Upregulation of ampC expression caused by mutations in peptidoglycan recycling genes such as ampD or ampG in various bacteria with inducible ampC genes is well studied (36, 37). An in vitro transposon mutagenesis study also found insertions in mpl in Pseudomonas aeruginosa causing AmpR-dependent upregulation of chromosomal ampC and reduced susceptibility to β-lactams (38). A recent report also described the emergence of mpl mutations in P. aeruginosa during serial passaging in the presence of aztreonam (39). The remaining NB29289-derived mutant had an ampD encoding a previously reported W7G substitution shown to upregulate chromosomal ampC expression in some Gram-negative bacteria (40). The MIC of LYS228 increased to 16 for this mutant (Table 1).

FIG 1
  • Open in new tab
  • Download powerpoint
FIG 1

Constitutive blaDHA-1 expression in mpl mutants selected in vitro from K. pneumoniae NB29293 (NB29293-CDK0021 and NB29293-CDK0022) and in clinical isolates harboring alterations in mpl (NB29338, NB29352, NB29353, and NB29393). RT-qPCR was done as previously described (33), and expression analysis was done using the 2−ΔΔCT method (42) relative to uninduced strain NB29293. Two additional clinical isolates harboring wild-type mpl (NB29263 and NB29379) are included for comparison. Data are averages from two biological replicates. Induction of blaDHA-1 transcription (3- to 7-fold) was seen for NB29293 cells exposed to LYS228 at a MIC of 1 μg/ml (data not shown).

The majority of the clinical isolates studied here encoded an Mpl protein identical to that of reference strain ATCC 43816 (32), which does not harbor blaDHA-1. However, isolate NB29353 encoded MplG68D, and mpl from isolates NB29338, NB29352, and NB29393 contained large deletions, frame shifts, and amino acid substitutions (Table 1). Expression of blaDHA-1 was upregulated 90-fold in NB29338 and >300-fold in NB29352, NB29353, and NB29393 relative to strains NB29293, NB29263, and NB29379, which all harbored wild-type mpl (Fig. 1). NB29338, NB29352, NB29353, and NB29393 were also among the least susceptible to LYS228 of the blaDHA-1-containing K. pneumoniae strains tested (Table 1).

In conclusion, this study suggests that inducible blaDHA-1 can decrease susceptibility to LYS228 in some K. pneumoniae clinical isolates, presumably depending on the presence of additional resistance mechanisms in these strains. In cases where β-lactamases may impact the clinical utility of LYS228, pairing with an appropriate β-lactamase inhibitor may restore susceptibility. We also uncovered a novel mechanism of upregulation of plasmid-borne blaDHA-1 expression via chromosomal mpl mutations and show that these mutations occur in clinical isolates. To our knowledge, this is the first report of this mechanism in K. pneumoniae. Delineating the mechanism by which defects in Mpl upregulate DHA-1 expression warrants further study.

ACKNOWLEDGMENTS

We thank Dave Barkan and Peter Skewes-Cox for bioinformatics assistance and Daryl Richie for helpful discussion.

FOOTNOTES

    • Received 6 June 2018.
    • Returned for modification 1 July 2018.
    • Accepted 27 July 2018.
    • Accepted manuscript posted online 30 July 2018.
  • For a companion article on this topic, see https://doi.org/10.1128/AAC.01200-18.

REFERENCES

  1. 1.↵
    1. Bush K
    . 2013. Proliferation and significance of clinically relevant beta-lactamases. Ann N Y Acad Sci 1277:84–90. doi:10.1111/nyas.12023.
    OpenUrlCrossRefPubMedWeb of Science
  2. 2.↵
    1. Watkins RR,
    2. Bonomo RA
    . 2016. Overview: global and local impact of antibiotic resistance. Infect Dis Clin North Am 30:313–322. doi:10.1016/j.idc.2016.02.001.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Shlaes DM,
    2. Bradford PA
    . 2018. Antibiotics-from where to where? How the antibiotic miracle is threatened by resistance and a broken market and what we can do about it. Pathog Immun 13:19–43.
    OpenUrl
  4. 4.↵
    1. Walsh TR,
    2. Weeks J,
    3. Livermore DM,
    4. Toleman MA
    . 2011. Dissemination of NDM-1 positive bacteria in the New Delhi environment and its implications for human health: an environmental point prevalence study. Lancet Infect Dis 11:355–362. doi:10.1016/S1473-3099(11)70059-7.
    OpenUrlCrossRefPubMedWeb of Science
  5. 5.↵
    1. Drawz SM,
    2. Papp-Wallace KM,
    3. Bonomo RA
    . 2014. New beta-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob Agents Chemother 58:1835–1846. doi:10.1128/AAC.00826-13.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Felici A,
    2. Amicosante G
    . 1995. Kinetic analysis of extension of substrate specificity with Xanthomonas maltophilia, Aeromonas hydrophila, and Bacillus cereus metallo-beta-lactamases. Antimicrob Agents Chemother 39:192–199. doi:10.1128/AAC.39.1.192.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Felici A,
    2. Amicosante G,
    3. Oratore A,
    4. Strom R,
    5. Ledent P,
    6. Joris B,
    7. Fanuel L,
    8. Frere JM
    . 1993. An overview of the kinetic parameters of class B beta-lactamases. Biochem J 291(Part 1):151–155. doi:10.1042/bj2910151.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Reck F,
    2. Bermingham A,
    3. Blais J,
    4. Capka V,
    5. Cariaga T,
    6. Casarez A,
    7. Colvin R,
    8. Dean CR,
    9. Fekete A,
    10. Gong W,
    11. Growcott E,
    12. Guo H,
    13. Jones AK,
    14. Li C,
    15. Li F,
    16. Lin X,
    17. Lindvall M,
    18. Lopez S,
    19. McKenney D,
    20. Metzger L,
    21. Moser HE,
    22. Prathapam R,
    23. Rasper D,
    24. Rudewicz P,
    25. Sethuraman V,
    26. Shen X,
    27. Shaul J,
    28. Simmons RL,
    29. Tashiro K,
    30. Tang D,
    31. Tjandra M,
    32. Turner N,
    33. Uehara T,
    34. Vitt C,
    35. Whitebread S,
    36. Yifru A,
    37. Zang X,
    38. Zhu Q
    . 2018. Optimization of novel monobactams with activity against carbapenem-resistant Enterobacteriaceae–identification of LYS228. Bioorg Med Chem Lett 28:748–755. doi:10.1016/j.bmcl.2018.01.006.
    OpenUrlCrossRef
  9. 9.↵
    1. Blais J,
    2. Lopez S,
    3. Li C,
    4. Ruzin A,
    5. Ranjitkar S,
    6. Dean CR,
    7. Leeds JA,
    8. Casarez A,
    9. Simmons RL,
    10. Reck F
    . 23 July 2018. In vitro activity of LYS228, a novel monobactam antibiotic, against multidrug-resistant Enterobacteriaceae. Antimicrob Agents Chemother doi:10.1128/AAC.00552-18.
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    1. Compain F,
    2. Decre D,
    3. Fulgencio JP,
    4. Berraho S,
    5. Arlet G,
    6. Verdet C
    . 2014. Molecular characterization of DHA-1-producing Klebsiella pneumoniae isolates collected during a 4-year period in an intensive care unit. Diagn Microbiol Infect Dis 80:159–161. doi:10.1016/j.diagmicrobio.2014.06.009.
    OpenUrlCrossRef
  11. 11.↵
    1. Voulgari E,
    2. Poulou A,
    3. Dimitroulia E,
    4. Politi L,
    5. Ranellou K,
    6. Gennimata V,
    7. Markou F,
    8. Pournaras S,
    9. Tsakris A
    . 2015. Emergence of OXA-162 carbapenemase- and DHA-1 AmpC cephalosporinase-producing sequence type 11 Klebsiella pneumoniae causing community-onset infection in Greece. Antimicrob Agents Chemother 60:1862–1864. doi:10.1128/AAC.01514-15.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Chudackova E,
    2. Bergerova T,
    3. Fajfrlik K,
    4. Cervena D,
    5. Urbaskova P,
    6. Empel J,
    7. Gniadkowski M,
    8. Hrabak J
    . 2010. Carbapenem-nonsusceptible strains of Klebsiella pneumoniae producing SHV-5 and/or DHA-1 beta-lactamases in a Czech hospital. FEMS Microbiol Lett 309:62–70.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Empel J,
    2. Hrabak J,
    3. Kozinska A,
    4. Bergerova T,
    5. Urbaskova P,
    6. Kern-Zdanowicz I,
    7. Gniadkowski M
    . 2010. DHA-1-producing Klebsiella pneumoniae in a teaching hospital in the Czech Republic. Microb Drug Resist 16:291–295. doi:10.1089/mdr.2010.0030.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Livermore DM,
    2. Mushtaq S,
    3. Meunier D,
    4. Hopkins KL,
    5. Hill R,
    6. Adkin R,
    7. Chaudhry A,
    8. Pike R,
    9. Staves P,
    10. Woodford N
    , Committee BRSS. 2017. Activity of ceftolozane/tazobactam against surveillance and “problem” Enterobacteriaceae, Pseudomonas aeruginosa and non-fermenters from the British Isles. J Antimicrob Chemother 72:2278–2289. doi:10.1093/jac/dkx136.
    OpenUrlCrossRef
  15. 15.↵
    1. Ingti B,
    2. Paul D,
    3. Maurya AP,
    4. Bora D,
    5. Chanda DD,
    6. Chakravarty A,
    7. Bhattacharjee A
    . 2017. Occurrence of bla DHA-1 mediated cephalosporin resistance in Escherichia coli and their transcriptional response against cephalosporin stress: a report from India. Ann Clin Microbiol Antimicrob 16:13. doi:10.1186/s12941-017-0189-x.
    OpenUrlCrossRef
  16. 16.↵
    1. Verdet C,
    2. Benzerara Y,
    3. Gautier V,
    4. Adam O,
    5. Ould-Hocine Z,
    6. Arlet G
    . 2006. Emergence of DHA-1-producing Klebsiella spp. in the Parisian region: genetic organization of the ampC and ampR genes originating from Morganella morganii. Antimicrob Agents Chemother 50:607–617. doi:10.1128/AAC.50.2.607-617.2006.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. Hennequin C,
    2. Robin F,
    3. Cabrolier N,
    4. Bonnet R,
    5. Forestier C
    . 2012. Characterization of a DHA-1-producing Klebsiella pneumoniae strain involved in an outbreak and role of the AmpR regulator in virulence. Antimicrob Agents Chemother 56:288–294. doi:10.1128/AAC.00164-11.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    1. Abdalhamid B,
    2. Albunayan S,
    3. Shaikh A,
    4. Elhadi N,
    5. Aljindan R
    . 2017. Prevalence study of plasmid-mediated AmpC beta-lactamases in Enterobacteriaceae lacking inducible ampC from Saudi hospitals. J Med Microbiol 66:1286–1290. doi:10.1099/jmm.0.000504.
    OpenUrlCrossRef
  19. 19.↵
    1. Vanwynsberghe T,
    2. Verhamme K,
    3. Raymaekers M,
    4. Cartuyvels R,
    5. Van Vaerenbergh K,
    6. Boel A,
    7. De Beenhouwer H
    . 2009. A large outbreak of Klebsiella pneumoniae (DHA-1 and SHV-11 positive): importance of detection and treatment of ampC B-lactamases. Open Infect Dis J 3:55–60. doi:10.2174/1874279300903010055.
    OpenUrlCrossRef
  20. 20.↵
    1. Jean SS,
    2. Hsueh PR
    , SMART Asia-Pacific Group. 2017. Distribution of ESBLs, AmpC beta-lactamases and carbapenemases among Enterobacteriaceae isolates causing intra-abdominal and urinary tract infections in the Asia-Pacific region during 2008–14: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART). J Antimicrob Chemother 72:166–171. doi:10.1093/jac/dkw398.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Lin WP,
    2. Wang JT,
    3. Chang SC,
    4. Chang FY,
    5. Fung CP,
    6. Chuang YC,
    7. Chen YS,
    8. Shiau YR,
    9. Tan MC,
    10. Wang HY,
    11. Lai JF,
    12. Huang IW,
    13. Lauderdale TL
    . 2016. The antimicrobial susceptibility of Klebsiella pneumoniae from community settings in Taiwan, a trend analysis. Sci Rep 6:36280. doi:10.1038/srep36280.
    OpenUrlCrossRef
  22. 22.↵
    1. Hsieh WS,
    2. Wang NY,
    3. Feng JA,
    4. Weng LC,
    5. Wu HH
    . 2015. Identification of DHA-23, a novel plasmid-mediated and inducible AmpC beta-lactamase from Enterobacteriaceae in Northern Taiwan. Front Microbiol 6:436. doi:10.3389/fmicb.2015.00436.
    OpenUrlCrossRef
  23. 23.↵
    1. Yoo JS,
    2. Byeon J,
    3. Yang J,
    4. Yoo JI,
    5. Chung GT,
    6. Lee YS
    . 2010. High prevalence of extended-spectrum beta-lactamases and plasmid-mediated AmpC beta-lactamases in Enterobacteriaceae isolated from long-term care facilities in Korea. Diagn Microbiol Infect Dis 67:261–265. doi:10.1016/j.diagmicrobio.2010.02.012.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Liu XQ,
    2. Liu YR
    . 2016. Detection and genotype analysis of AmpC beta-lactamase in Klebsiella pneumoniae from tertiary hospitals. Exp Ther Med 12:480–484. doi:10.3892/etm.2016.3295.
    OpenUrlCrossRef
  25. 25.↵
    1. Barnaud G,
    2. Arlet G,
    3. Verdet C,
    4. Gaillot O,
    5. Lagrange PH,
    6. Philippon A
    . 1998. Salmonella enteritidis: AmpC plasmid-mediated inducible beta-lactamase (DHA-1) with an ampR gene from Morganella morganii. Antimicrob Agents Chemother 42:2352–2358.
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    1. Philippon A,
    2. Arlet G,
    3. Jacoby GA
    . 2002. Plasmid-determined AmpC-type beta-lactamases. Antimicrob Agents Chemother 46:1–11. doi:10.1128/AAC.46.1.1-11.2002.
    OpenUrlFREE Full Text
  27. 27.↵
    1. Shin SY,
    2. Bae IK,
    3. Kim J,
    4. Jeong SH,
    5. Yong D,
    6. Kim JM,
    7. Lee K
    . 2012. Resistance to carbapenems in sequence type 11 Klebsiella pneumoniae is related to DHA-1 and loss of OmpK35 and/or OmpK36. J Med Microbiol 61:239–245. doi:10.1099/jmm.0.037036-0.
    OpenUrlCrossRefPubMed
  28. 28.↵
    1. Tsai YK,
    2. Liou CH,
    3. Fung CP,
    4. Lin JC,
    5. Siu LK
    . 2013. Single or in combination antimicrobial resistance mechanisms of Klebsiella pneumoniae contribute to varied susceptibility to different carbapenems. PLoS One 8:e79640. doi:10.1371/journal.pone.0079640.
    OpenUrlCrossRef
  29. 29.↵
    1. Vanwynsberghe T,
    2. Verhamme K,
    3. Raymaekers M,
    4. Cartuyvels R,
    5. Boel A,
    6. De Beenhouwer H
    . 2007. Outbreak of Klebsiella pneumoniae strain harbouring an AmpC (DHA-1) and a blaSHV-11 in a Belgian hospital, August-December 2006. Euro Surveill 12:E070201–E070203.
    OpenUrl
  30. 30.↵
    1. Reuland EA,
    2. Hays JP,
    3. de Jongh DM,
    4. Abdelrehim E,
    5. Willemsen I,
    6. Kluytmans JA,
    7. Savelkoul PH,
    8. Vandenbroucke-Grauls CM,
    9. al Naiemi N
    . 2014. Detection and occurrence of plasmid-mediated AmpC in highly resistant gram-negative rods. PLoS One 9:e91396. doi:10.1371/journal.pone.0091396.
    OpenUrlCrossRef
  31. 31.↵
    1. Moland ES,
    2. Hanson ND,
    3. Black JA,
    4. Hossain A,
    5. Song W,
    6. Thomson KS
    . 2006. Prevalence of newer beta-lactamases in gram-negative clinical isolates collected in the United States from 2001 to 2002. J Clin Microbiol 44:3318–3324. doi:10.1128/JCM.00756-06.
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    1. Broberg CA,
    2. Wu W,
    3. Cavalcoli JD,
    4. Miller VL,
    5. Bachman MA
    . 2014. Complete genome sequence of Klebsiella pneumoniae strain ATCC 43816 KPPR1, a rifampin-resistant mutant commonly used in animal, genetic, and molecular biology studies. Genome Announc 22:e00924-14.
  33. 33.↵
    1. Dean CR,
    2. Barkan DT,
    3. Bermingham A,
    4. Blais J,
    5. Casey F,
    6. Casarez A,
    7. Colvin R,
    8. Fuller J,
    9. Jones AK,
    10. Li C,
    11. Lopez S,
    12. Metzger LE, IV,
    13. Mostafavi M,
    14. Prathapam R,
    15. Rasper D,
    16. Reck F,
    17. Ruzin A,
    18. Shaul J,
    19. Shen X,
    20. Simmons RL,
    21. Skewes-Cox P,
    22. Takeoka KT,
    23. Tamrakar P,
    24. Uehara T,
    25. Wei J-R
    . 2018. Mode of action of the monobactam LYS228 and mechanisms decreasing in vitro susceptibility in Escherichia coli and Klebsiella pneumoniae. Antimicrob Agents Chemother 62:e01200-18. doi:10.1128/AAC.01200-18.
    OpenUrlAbstract/FREE Full Text
  34. 34.↵
    1. Mengin-Lecreulx D,
    2. van Heijenoort J,
    3. Park JT
    . 1996. Identification of the mpl gene encoding UDP-N-acetylmuramate: l-alanyl-gamma-d-glutamyl-meso-diaminopimelate ligase in Escherichia coli and its role in recycling of cell wall peptidoglycan. J Bacteriol 178:5347–5352. doi:10.1128/jb.178.18.5347-5352.1996.
    OpenUrlAbstract/FREE Full Text
  35. 35.↵
    1. Uehara T,
    2. Park JT
    . 15 October 2008, posting date. Peptidoglycan recycling. EcoSal Plus 2008 doi:10.1128/ecosalplus.4.7.1.5.
    OpenUrlCrossRef
  36. 36.↵
    1. Jones RN,
    2. Baquero F,
    3. Privitera G,
    4. Inoue M,
    5. Wiedermann B
    . 1997. Inducible B-lactamase-mediated resistance to third-generation cephalosporins. Clin Microbiol Infect 3:S7–S18. doi:10.1111/j.1469-0691.1997.tb00643.x.
    OpenUrlCrossRef
  37. 37.↵
    1. Luan Y,
    2. Li GL,
    3. Duo LB,
    4. Wang WP,
    5. Wang CY,
    6. Zhang HG,
    7. He F,
    8. He X,
    9. Chen SJ,
    10. Luo DT
    . 2015. DHA-1 plasmid-mediated AmpC beta-lactamase expression and regulation of Klebsiella pneumoniae isolates. Mol Med Rep 11:3069–3077. doi:10.3892/mmr.2014.3054.
    OpenUrlCrossRef
  38. 38.↵
    1. Tsutsumi Y,
    2. Tomita H,
    3. Tanimoto K
    . 2013. Identification of novel genes responsible for overexpression of ampC in Pseudomonas aeruginosa PAO1. Antimicrob Agents Chemother 57:5987–5993. doi:10.1128/AAC.01291-13.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    1. Jorth P,
    2. McLean K,
    3. Ratjen A,
    4. Secor PR,
    5. Bautista GE,
    6. Ravishankar S,
    7. Rezayat A,
    8. Garudathri J,
    9. Harrison JJ,
    10. Harwood RA,
    11. Penewit K,
    12. Waalkes A,
    13. Singh PK,
    14. Salipante SJ
    . 2017. Evolved aztreonam resistance is multifactorial and can produce hypervirulence in Pseudomonas aeruginosa. mBio 8:e00517-17. doi:10.1128/mBio.00517-17.
    OpenUrlAbstract/FREE Full Text
  40. 40.↵
    1. Petrosino JF,
    2. Pendleton AR,
    3. Weiner JH,
    4. Rosenberg SM
    . 2002. Chromosomal system for studying AmpC-mediated β-lactam resistance mutation in Escherichia coli. Antimicrob Agents Chemother 46:1535–1539. doi:10.1128/AAC.46.5.1535-1539.2002.
    OpenUrlAbstract/FREE Full Text
  41. 41.
    CLSI. 2015. Methods for dilution antimicrobial susceptibility tests for bacterial that grow aerobically. Approved Standard, 10th ed, supplement M07-A10. Clinical and Laboratory Standards Institute, Wayne, PA.
  42. 42.↵
    1. Livak KJ,
    2. Schmittgen TD
    . 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408. doi:10.1006/meth.2001.1262.
    OpenUrlCrossRefPubMedWeb of Science
  • Copyright © 2018 American Society for Microbiology.

All Rights Reserved.

View Abstract
PreviousNext
Back to top
Download PDF
Citation Tools
Impact of Inducible blaDHA-1 on Susceptibility of Klebsiella pneumoniae Clinical Isolates to LYS228 and Identification of Chromosomal mpl and ampD Mutations Mediating Upregulation of Plasmid-Borne blaDHA-1 Expression
Adriana K. Jones, Srijan Ranjitkar, Sara Lopez, Cindy Li, Johanne Blais, Folkert Reck, Charles R. Dean
Antimicrobial Agents and Chemotherapy Sep 2018, 62 (10) e01202-18; DOI: 10.1128/AAC.01202-18

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Print

Alerts
Sign In to Email Alerts with your Email Address
Email

Thank you for sharing this Antimicrobial Agents and Chemotherapy article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Impact of Inducible blaDHA-1 on Susceptibility of Klebsiella pneumoniae Clinical Isolates to LYS228 and Identification of Chromosomal mpl and ampD Mutations Mediating Upregulation of Plasmid-Borne blaDHA-1 Expression
(Your Name) has forwarded a page to you from Antimicrobial Agents and Chemotherapy
(Your Name) thought you would be interested in this article in Antimicrobial Agents and Chemotherapy.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Impact of Inducible blaDHA-1 on Susceptibility of Klebsiella pneumoniae Clinical Isolates to LYS228 and Identification of Chromosomal mpl and ampD Mutations Mediating Upregulation of Plasmid-Borne blaDHA-1 Expression
Adriana K. Jones, Srijan Ranjitkar, Sara Lopez, Cindy Li, Johanne Blais, Folkert Reck, Charles R. Dean
Antimicrobial Agents and Chemotherapy Sep 2018, 62 (10) e01202-18; DOI: 10.1128/AAC.01202-18
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Top
  • Article
    • ABSTRACT
    • TEXT
    • ACKNOWLEDGMENTS
    • FOOTNOTES
    • REFERENCES
  • Figures & Data
  • Info & Metrics
  • PDF

KEYWORDS

DHA-1
Klebsiella
LYS228
beta-lactamases
peptidoglycan
plasmid

Related Articles

Cited By...

About

  • About AAC
  • Editor in Chief
  • Editorial Board
  • Policies
  • For Reviewers
  • For the Media
  • For Librarians
  • For Advertisers
  • Alerts
  • AAC Podcast
  • RSS
  • FAQ
  • Permissions
  • Journal Announcements

Authors

  • ASM Author Center
  • Submit a Manuscript
  • Article Types
  • Ethics
  • Contact Us

Follow #AACJournal

@ASMicrobiology

       

ASM Journals

ASM journals are the most prominent publications in the field, delivering up-to-date and authoritative coverage of both basic and clinical microbiology.

About ASM | Contact Us | Press Room

 

ASM is a member of

Scientific Society Publisher Alliance

 

American Society for Microbiology
1752 N St. NW
Washington, DC 20036
Phone: (202) 737-3600

Copyright © 2021 American Society for Microbiology | Privacy Policy | Website feedback

Print ISSN: 0066-4804; Online ISSN: 1098-6596