Mis-annotations of a promising antibiotic target in high-priority gram-negative pathogens

Rachael E. Impey, Mihwa Lee, Daniel A. Hawkins, J. Mark Sutton, Santosh Panjikar, Matthew A. Perugini*, Tatiana P. Soares da Costa

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

The rise of antibiotic resistance combined with the lack of new products entering the market has led to bacterial infections becoming one of the biggest threats to global health. Therefore, there is an urgent need to identify novel antibiotic targets, such as dihydrodipicolinate synthase (DHDPS), an enzyme involved in the production of essential metabolites in cell wall and protein synthesis. Here, we utilised a 7-residue sequence motif to identify mis-annotation of multiple DHDPS genes in the high-priority Gram-negative bacteria Acinetobacter baumannii and Klebsiella pneumoniae. We subsequently confirmed these mis-annotations using a combination of enzyme kinetics and X-ray crystallography. Thus, this study highlights the need to ensure genes encoding promising drug targets, like DHDPS, are annotated correctly, especially for clinically important pathogens. PDB ID: 6UE0.

Original languageEnglish
Pages (from-to)1453-1463
Number of pages11
JournalFEBS Letters
Volume594
Issue number9
DOIs
Publication statusPublished - 1 May 2020

Bibliographical note

Funding Information:
TPSC would like to thank the National Health and Medical Research Council of Australia (APP1091976) and Australian Research Council (DE190100806) for fellowship and funding support, and MAP and SP the Australian Research Council for funding support (DP150103313). REI is supported by an Australian Research Training scholarship and acknowledges the British Society for Antimicrobial Chemotherapy for funding support. ML is supported by the Tracey Banivanua Mar fellowship from La Trobe University. We thank Dr. Janni Christensen for the insurgent technical support. We acknowledge the use of the MX2 beamline at the Australian Synchrotron and the CSIRO Collaborative Crystallisation Centre (www.csiro/C3; Melbourne, Australia). We also thank the La Trobe University Comprehensive Proteomics Platform for providing infrastructure support.

Funding Information:
TPSC would like to thank the National Health and Medical Research Council of Australia (APP1091976) and Australian Research Council (DE190100806) for fellowship and funding support, and MAP and SP the Australian Research Council for funding support (DP150103313). REI is supported by an Australian Research Training scholarship and acknowledges the British Society for Antimicrobial Chemotherapy for funding support. ML is supported by the Tracey Banivanua Mar fellowship from La Trobe University. We thank Dr. Janni Christensen for the insurgent technical support. We acknowledge the use of the MX2 beamline at the Australian Synchrotron and the CSIRO Collaborative Crystallisation Centre ( www.csiro/ C3 ; Melbourne, Australia). We also thank the La Trobe University Comprehensive Proteomics Platform for providing infrastructure support.

Publisher Copyright:
© 2020 Federation of European Biochemical Societies

Keywords

  • 4-hydroxy-tetrahydrodipicolinate synthase
  • antibiotic resistance
  • cell wall
  • diaminopimelate pathway
  • lysine

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