From microbial gene essentiality to novel antimicrobial drug targets
Background: Bacterial respiratory tract infections, mainly caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are among the leading causes of global mortality and morbidity. Increased resistance of these pathogens to existing antibiotics necessitates the search for...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Journal Article |
| Language: | English |
| Published: |
BMC
2014
|
| Subjects: | |
| Online Access: | http://hdl.handle.net/20.500.11937/80737 |
| _version_ | 1848764261991448576 |
|---|---|
| author | Mobegi, Fredrick van Hijum, S.A.F.T. Burghout, P. Bootsma, H.J. de Vries, S.P.W. van der Gaast-de Jongh, C.E. Simonetti, E. Langereis, J.D. Hermans, P.W.M. de Jonge, M.I. Zomer, A. |
| author_facet | Mobegi, Fredrick van Hijum, S.A.F.T. Burghout, P. Bootsma, H.J. de Vries, S.P.W. van der Gaast-de Jongh, C.E. Simonetti, E. Langereis, J.D. Hermans, P.W.M. de Jonge, M.I. Zomer, A. |
| author_sort | Mobegi, Fredrick |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Background: Bacterial respiratory tract infections, mainly caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are among the leading causes of global mortality and morbidity. Increased resistance of these pathogens to existing antibiotics necessitates the search for novel targets to develop potent antimicrobials.
Result: Here, we report a proof of concept study for the reliable identification of potential drug targets in these human respiratory pathogens by combining high-density transposon mutagenesis, high-throughput sequencing, and integrative genomics. Approximately 20% of all genes in these three species were essential for growth and viability, including 128 essential and conserved genes, part of 47 metabolic pathways. By comparing these essential genes to the human genome, and a database of genes from commensal human gut microbiota, we identified and excluded potential drug targets in respiratory tract pathogens that will have off-target effects in the host, or disrupt the natural host microbiota. We propose 249 potential drug targets, 67 of which are targets for 75 FDA-approved antimicrobials and 35 other researched small molecule inhibitors. Two out of four selected novel targets were experimentally validated, proofing the concept.
Conclusion: Here we have pioneered an attempt in systematically combining the power of high-density transposon mutagenesis, high-throughput sequencing, and integrative genomics to discover potential drug targets at genome-scale. By circumventing the time-consuming and expensive laboratory screens traditionally used to select potential drug targets, our approach provides an attractive alternative that could accelerate the much needed discovery of novel antimicrobials. |
| first_indexed | 2025-11-14T11:16:33Z |
| format | Journal Article |
| id | curtin-20.500.11937-80737 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T11:16:33Z |
| publishDate | 2014 |
| publisher | BMC |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-807372021-01-07T07:46:47Z From microbial gene essentiality to novel antimicrobial drug targets Mobegi, Fredrick van Hijum, S.A.F.T. Burghout, P. Bootsma, H.J. de Vries, S.P.W. van der Gaast-de Jongh, C.E. Simonetti, E. Langereis, J.D. Hermans, P.W.M. de Jonge, M.I. Zomer, A. Science & Technology Life Sciences & Biomedicine Biotechnology & Applied Microbiology Genetics & Heredity FATTY-ACID BIOSYNTHESIS STREPTOCOCCUS-PNEUMONIAE HAEMOPHILUS-INFLUENZAE MORAXELLA-CATARRHALIS CARBONIC-ANHYDRASE GENOME IDENTIFICATION RESISTANCE PATHWAY GROWTH Background: Bacterial respiratory tract infections, mainly caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are among the leading causes of global mortality and morbidity. Increased resistance of these pathogens to existing antibiotics necessitates the search for novel targets to develop potent antimicrobials. Result: Here, we report a proof of concept study for the reliable identification of potential drug targets in these human respiratory pathogens by combining high-density transposon mutagenesis, high-throughput sequencing, and integrative genomics. Approximately 20% of all genes in these three species were essential for growth and viability, including 128 essential and conserved genes, part of 47 metabolic pathways. By comparing these essential genes to the human genome, and a database of genes from commensal human gut microbiota, we identified and excluded potential drug targets in respiratory tract pathogens that will have off-target effects in the host, or disrupt the natural host microbiota. We propose 249 potential drug targets, 67 of which are targets for 75 FDA-approved antimicrobials and 35 other researched small molecule inhibitors. Two out of four selected novel targets were experimentally validated, proofing the concept. Conclusion: Here we have pioneered an attempt in systematically combining the power of high-density transposon mutagenesis, high-throughput sequencing, and integrative genomics to discover potential drug targets at genome-scale. By circumventing the time-consuming and expensive laboratory screens traditionally used to select potential drug targets, our approach provides an attractive alternative that could accelerate the much needed discovery of novel antimicrobials. 2014 Journal Article http://hdl.handle.net/20.500.11937/80737 10.1186/1471-2164-15-958 English http://creativecommons.org/licenses/by/4.0/ BMC fulltext |
| spellingShingle | Science & Technology Life Sciences & Biomedicine Biotechnology & Applied Microbiology Genetics & Heredity FATTY-ACID BIOSYNTHESIS STREPTOCOCCUS-PNEUMONIAE HAEMOPHILUS-INFLUENZAE MORAXELLA-CATARRHALIS CARBONIC-ANHYDRASE GENOME IDENTIFICATION RESISTANCE PATHWAY GROWTH Mobegi, Fredrick van Hijum, S.A.F.T. Burghout, P. Bootsma, H.J. de Vries, S.P.W. van der Gaast-de Jongh, C.E. Simonetti, E. Langereis, J.D. Hermans, P.W.M. de Jonge, M.I. Zomer, A. From microbial gene essentiality to novel antimicrobial drug targets |
| title | From microbial gene essentiality to novel antimicrobial drug targets |
| title_full | From microbial gene essentiality to novel antimicrobial drug targets |
| title_fullStr | From microbial gene essentiality to novel antimicrobial drug targets |
| title_full_unstemmed | From microbial gene essentiality to novel antimicrobial drug targets |
| title_short | From microbial gene essentiality to novel antimicrobial drug targets |
| title_sort | from microbial gene essentiality to novel antimicrobial drug targets |
| topic | Science & Technology Life Sciences & Biomedicine Biotechnology & Applied Microbiology Genetics & Heredity FATTY-ACID BIOSYNTHESIS STREPTOCOCCUS-PNEUMONIAE HAEMOPHILUS-INFLUENZAE MORAXELLA-CATARRHALIS CARBONIC-ANHYDRASE GENOME IDENTIFICATION RESISTANCE PATHWAY GROWTH |
| url | http://hdl.handle.net/20.500.11937/80737 |