---
_id: '10271'
abstract:
- lang: eng
text: Understanding interactions between antibiotics used in combination is an important
theme in microbiology. Using the interactions between the antifolate drug trimethoprim
and the ribosome-targeting antibiotic erythromycin in Escherichia coli as a model,
we applied a transcriptomic approach for dissecting interactions between two antibiotics
with different modes of action. When trimethoprim and erythromycin were combined,
the transcriptional response of genes from the sulfate reduction pathway deviated
from the dominant effect of trimethoprim on the transcriptome. We successfully
altered the drug interaction from additivity to suppression by increasing the
sulfate level in the growth environment and identified sulfate reduction as an
important metabolic determinant that shapes the interaction between the two drugs.
Our work highlights the potential of using prioritization of gene expression patterns
as a tool for identifying key metabolic determinants that shape drug-drug interactions.
We further demonstrated that the sigma factor-binding protein gene crl shapes
the interactions between the two antibiotics, which provides a rare example of
how naturally occurring variations between strains of the same bacterial species
can sometimes generate very different drug interactions.
acknowledgement: High-throughput sequencing data were generated by the Vienna BioCenter
Core Facilities. The authors would like to thank Karin Mitosch, Bor Kavcic, and
Nadine Kraupner for their constructive feedback. The authors would also like to
thank Gertraud Stift, Julia Flor, Renate Srsek, Agnieszka Wiktor, and Booshini Fernando
for technical support.
article_number: '760017'
article_processing_charge: No
article_type: original
author:
- first_name: Qin
full_name: Qi, Qin
id: 3B22D412-F248-11E8-B48F-1D18A9856A87
last_name: Qi
orcid: 0000-0002-6148-2416
- first_name: S. Andreas
full_name: Angermayr, S. Andreas
last_name: Angermayr
- first_name: Mark Tobias
full_name: Bollenbach, Mark Tobias
id: 3E6DB97A-F248-11E8-B48F-1D18A9856A87
last_name: Bollenbach
orcid: 0000-0003-4398-476X
citation:
ama: Qi Q, Angermayr SA, Bollenbach MT. Uncovering Key Metabolic Determinants of
the Drug Interactions Between Trimethoprim and Erythromycin in Escherichia coli.
Frontiers in Microbiology. 2021;12. doi:10.3389/fmicb.2021.760017
apa: Qi, Q., Angermayr, S. A., & Bollenbach, M. T. (2021). Uncovering Key Metabolic
Determinants of the Drug Interactions Between Trimethoprim and Erythromycin in
Escherichia coli. Frontiers in Microbiology. Frontiers. https://doi.org/10.3389/fmicb.2021.760017
chicago: Qi, Qin, S. Andreas Angermayr, and Mark Tobias Bollenbach. “Uncovering
Key Metabolic Determinants of the Drug Interactions Between Trimethoprim and Erythromycin
in Escherichia Coli.” Frontiers in Microbiology. Frontiers, 2021. https://doi.org/10.3389/fmicb.2021.760017.
ieee: Q. Qi, S. A. Angermayr, and M. T. Bollenbach, “Uncovering Key Metabolic Determinants
of the Drug Interactions Between Trimethoprim and Erythromycin in Escherichia
coli,” Frontiers in Microbiology, vol. 12. Frontiers, 2021.
ista: Qi Q, Angermayr SA, Bollenbach MT. 2021. Uncovering Key Metabolic Determinants
of the Drug Interactions Between Trimethoprim and Erythromycin in Escherichia
coli. Frontiers in Microbiology. 12, 760017.
mla: Qi, Qin, et al. “Uncovering Key Metabolic Determinants of the Drug Interactions
Between Trimethoprim and Erythromycin in Escherichia Coli.” Frontiers in Microbiology,
vol. 12, 760017, Frontiers, 2021, doi:10.3389/fmicb.2021.760017.
short: Q. Qi, S.A. Angermayr, M.T. Bollenbach, Frontiers in Microbiology 12 (2021).
date_created: 2021-11-11T10:39:37Z
date_published: 2021-10-20T00:00:00Z
date_updated: 2023-08-14T11:43:23Z
day: '20'
ddc:
- '610'
doi: 10.3389/fmicb.2021.760017
ec_funded: 1
external_id:
isi:
- '000715997300001'
pmid:
- '34745067'
file:
- access_level: open_access
checksum: d41321748e9588dd3cf03e9a7222127f
content_type: application/pdf
creator: cchlebak
date_created: 2021-11-11T10:54:40Z
date_updated: 2021-11-11T10:54:40Z
file_id: '10272'
file_name: 2021_FrontiersMicrob_Qi.pdf
file_size: 2397203
relation: main_file
success: 1
file_date_updated: 2021-11-11T10:54:40Z
has_accepted_license: '1'
intvolume: ' 12'
isi: 1
keyword:
- microbiology
language:
- iso: eng
license: https://creativecommons.org/licenses/by/4.0/
month: '10'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 25E9AF9E-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: P27201-B22
name: Revealing the mechanisms underlying drug interactions
- _id: 25E83C2C-B435-11E9-9278-68D0E5697425
call_identifier: FP7
grant_number: '303507'
name: Optimality principles in responses to antibiotics
publication: Frontiers in Microbiology
publication_identifier:
eissn:
- 1664-302X
publication_status: published
publisher: Frontiers
quality_controlled: '1'
scopus_import: '1'
status: public
title: Uncovering Key Metabolic Determinants of the Drug Interactions Between Trimethoprim
and Erythromycin in Escherichia coli
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 12
year: '2021'
...
---
_id: '1552'
abstract:
- lang: eng
text: Antibiotic resistance carries a fitness cost that must be overcome in order
for resistance to persist over the long term. Compensatory mutations that recover
the functional defects associated with resistance mutations have been argued to
play a key role in overcoming the cost of resistance, but compensatory mutations
are expected to be rare relative to generally beneficial mutations that increase
fitness, irrespective of antibiotic resistance. Given this asymmetry, population
genetics theory predicts that populations should adapt by compensatory mutations
when the cost of resistance is large, whereas generally beneficial mutations should
drive adaptation when the cost of resistance is small. We tested this prediction
by determining the genomic mechanisms underpinning adaptation to antibiotic-free
conditions in populations of the pathogenic bacterium Pseudomonas aeruginosa that
carry costly antibiotic resistance mutations. Whole-genome sequencing revealed
that populations founded by high-cost rifampicin-resistant mutants adapted via
compensatory mutations in three genes of the RNA polymerase core enzyme, whereas
populations founded by low-cost mutants adapted by generally beneficial mutations,
predominantly in the quorum-sensing transcriptional regulator gene lasR. Even
though the importance of compensatory evolution in maintaining resistance has
been widely recognized, our study shows that the roles of general adaptation in
maintaining resistance should not be underestimated and highlights the need to
understand how selection at other sites in the genome influences the dynamics
of resistance alleles in clinical settings.
acknowledgement: "We thank the High-Throughput Genomics Group at the Wellcome Trust
Centre for Human Genetics funded by Wellcome\r\nTrust grant reference 090532/Z/09/Z
and Medical Research Council Hub grant no. G0900747 91070 for generation of the
high-throughput sequencing data. We thank Wook Kim and two anonymous reviewers for
their constructive feedback on previous versions of our manuscript."
article_number: '20152452'
author:
- first_name: Qin
full_name: Qi, Qin
id: 3B22D412-F248-11E8-B48F-1D18A9856A87
last_name: Qi
orcid: 0000-0002-6148-2416
- first_name: Macarena
full_name: Toll Riera, Macarena
last_name: Toll Riera
- first_name: Karl
full_name: Heilbron, Karl
last_name: Heilbron
- first_name: Gail
full_name: Preston, Gail
last_name: Preston
- first_name: R Craig
full_name: Maclean, R Craig
last_name: Maclean
citation:
ama: Qi Q, Toll Riera M, Heilbron K, Preston G, Maclean RC. The genomic basis of
adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa.
Proceedings of the Royal Society of London Series B Biological Sciences.
2016;283(1822). doi:10.1098/rspb.2015.2452
apa: Qi, Q., Toll Riera, M., Heilbron, K., Preston, G., & Maclean, R. C. (2016).
The genomic basis of adaptation to the fitness cost of rifampicin resistance in
Pseudomonas aeruginosa. Proceedings of the Royal Society of London Series B
Biological Sciences. Royal Society, The. https://doi.org/10.1098/rspb.2015.2452
chicago: Qi, Qin, Macarena Toll Riera, Karl Heilbron, Gail Preston, and R Craig
Maclean. “The Genomic Basis of Adaptation to the Fitness Cost of Rifampicin Resistance
in Pseudomonas Aeruginosa.” Proceedings of the Royal Society of London Series
B Biological Sciences. Royal Society, The, 2016. https://doi.org/10.1098/rspb.2015.2452.
ieee: Q. Qi, M. Toll Riera, K. Heilbron, G. Preston, and R. C. Maclean, “The genomic
basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas
aeruginosa,” Proceedings of the Royal Society of London Series B Biological
Sciences, vol. 283, no. 1822. Royal Society, The, 2016.
ista: Qi Q, Toll Riera M, Heilbron K, Preston G, Maclean RC. 2016. The genomic basis
of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa.
Proceedings of the Royal Society of London Series B Biological Sciences. 283(1822),
20152452.
mla: Qi, Qin, et al. “The Genomic Basis of Adaptation to the Fitness Cost of Rifampicin
Resistance in Pseudomonas Aeruginosa.” Proceedings of the Royal Society of
London Series B Biological Sciences, vol. 283, no. 1822, 20152452, Royal Society,
The, 2016, doi:10.1098/rspb.2015.2452.
short: Q. Qi, M. Toll Riera, K. Heilbron, G. Preston, R.C. Maclean, Proceedings
of the Royal Society of London Series B Biological Sciences 283 (2016).
date_created: 2018-12-11T11:52:40Z
date_published: 2016-01-13T00:00:00Z
date_updated: 2021-01-12T06:51:33Z
day: '13'
ddc:
- '570'
department:
- _id: ToBo
doi: 10.1098/rspb.2015.2452
file:
- access_level: open_access
checksum: 78ffe70c1c88af3856d31ca6b7195a27
content_type: application/pdf
creator: system
date_created: 2018-12-12T10:11:43Z
date_updated: 2020-07-14T12:45:02Z
file_id: '4899'
file_name: IST-2016-488-v1+1_20152452.full.pdf
file_size: 626804
relation: main_file
file_date_updated: 2020-07-14T12:45:02Z
has_accepted_license: '1'
intvolume: ' 283'
issue: '1822'
language:
- iso: eng
month: '01'
oa: 1
oa_version: Published Version
publication: Proceedings of the Royal Society of London Series B Biological Sciences
publication_status: published
publisher: Royal Society, The
publist_id: '5619'
pubrep_id: '488'
quality_controlled: '1'
scopus_import: 1
status: public
title: The genomic basis of adaptation to the fitness cost of rifampicin resistance
in Pseudomonas aeruginosa
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87
volume: 283
year: '2016'
...