Analysing the fitness cost of antibiotic resistance to identify targets for combination antimicrobials.
Journal
Nature microbiology
ISSN: 2058-5276
Titre abrégé: Nat Microbiol
Pays: England
ID NLM: 101674869
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
03
05
2021
accepted:
03
09
2021
pubmed:
27
10
2021
medline:
25
12
2021
entrez:
26
10
2021
Statut:
ppublish
Résumé
Mutations in the rifampicin (Rif)-binding site of RNA polymerase (RNAP) confer antibiotic resistance and often have global effects on transcription that compromise fitness and stress tolerance of resistant mutants. We suggested that the non-essential genome, through its impact on the bacterial transcription cycle, may represent an untapped source of targets for combination antimicrobial therapies. Using transposon sequencing, we carried out a genome-wide analysis of fitness cost in a clinically common rpoB H526Y mutant. We find that genes whose products enable increased transcription elongation rates compound the fitness costs of resistance whereas genes whose products function in cell wall synthesis and division mitigate it. We validate our findings by showing that the cell wall synthesis and division defects of rpoB H526Y result from an increased transcription elongation rate that is further exacerbated by the activity of the uracil salvage pathway and unresponsiveness of the mutant RNAP to the alarmone ppGpp. We applied our findings to identify drugs that inhibit more readily rpoB H526Y and other Rif
Identifiants
pubmed: 34697460
doi: 10.1038/s41564-021-00973-1
pii: 10.1038/s41564-021-00973-1
pmc: PMC9389595
mid: NIHMS1828175
doi:
Substances chimiques
Anti-Bacterial Agents
0
Bacterial Proteins
0
DNA-Directed RNA Polymerases
EC 2.7.7.6
Rifampin
VJT6J7R4TR
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1410-1423Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM126891
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI105129
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI099394
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007180
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI121244
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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