Importance of Core Genome Functions for an Extreme Antibiotic Resistance Trait

ABSTRACT Extreme antibiotic resistance in bacteria is associated with the expression of powerful inactivating enzymes and other functions encoded in accessory genomic elements. The contribution of core genome processes to high-level resistance in such bacteria has been unclear. In the work reported...

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Autores principales:	Larry A. Gallagher, Samuel A. Lee, Colin Manoil
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	AB5075 Tn-seq intrinsic resistance mutant library tobramycin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a451ed5ce73e44afafe67ad0c35c019e
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spelling	oai:doaj.org-article:a451ed5ce73e44afafe67ad0c35c019e2021-11-15T15:51:56ZImportance of Core Genome Functions for an Extreme Antibiotic Resistance Trait10.1128/mBio.01655-172150-7511https://doaj.org/article/a451ed5ce73e44afafe67ad0c35c019e2017-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01655-17https://doaj.org/toc/2150-7511ABSTRACT Extreme antibiotic resistance in bacteria is associated with the expression of powerful inactivating enzymes and other functions encoded in accessory genomic elements. The contribution of core genome processes to high-level resistance in such bacteria has been unclear. In the work reported here, we evaluated the relative importance of core and accessory functions for high-level resistance to the aminoglycoside tobramycin in the nosocomial pathogen Acinetobacter baumannii. Three lines of evidence establish the primacy of core functions in this resistance. First, in a genome scale mutant analysis using transposon sequencing and validation with 594 individual mutants, nearly all mutations reducing tobramycin resistance inactivated core genes, some with stronger phenotypes than those caused by the elimination of aminoglycoside-inactivating enzymes. Second, the core functions mediating resistance were nearly identical in the wild type and a deletion mutant lacking a genome resistance island that encodes the inactivating enzymes. Thus, most or all of the core resistance determinants important in the absence of the enzymes are also important in their presence. Third, reductions in tobramycin resistance caused by different core mutations were additive, and highly sensitive double and triple mutants (with 250-fold reductions in the MIC) that retained accessory resistance genes could be constructed. Core processes that contribute most strongly to intrinsic tobramycin resistance include phospholipid biosynthesis, phosphate regulation, and envelope homeostasis. IMPORTANCE The inexorable increase in bacterial antibiotic resistance threatens to undermine many of the procedures that transformed medicine in the last century. One strategy to meet the challenge antibiotic resistance poses is the development of drugs that undermine resistance. To identify potential targets for such adjuvants, we identified the functions underlying resistance to an important class of antibiotics for one of the most highly resistant pathogens known.Larry A. GallagherSamuel A. LeeColin ManoilAmerican Society for MicrobiologyarticleAB5075Tn-seqintrinsic resistancemutant librarytobramycinMicrobiologyQR1-502ENmBio, Vol 8, Iss 6 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	AB5075 Tn-seq intrinsic resistance mutant library tobramycin Microbiology QR1-502
spellingShingle	AB5075 Tn-seq intrinsic resistance mutant library tobramycin Microbiology QR1-502 Larry A. Gallagher Samuel A. Lee Colin Manoil Importance of Core Genome Functions for an Extreme Antibiotic Resistance Trait
description	ABSTRACT Extreme antibiotic resistance in bacteria is associated with the expression of powerful inactivating enzymes and other functions encoded in accessory genomic elements. The contribution of core genome processes to high-level resistance in such bacteria has been unclear. In the work reported here, we evaluated the relative importance of core and accessory functions for high-level resistance to the aminoglycoside tobramycin in the nosocomial pathogen Acinetobacter baumannii. Three lines of evidence establish the primacy of core functions in this resistance. First, in a genome scale mutant analysis using transposon sequencing and validation with 594 individual mutants, nearly all mutations reducing tobramycin resistance inactivated core genes, some with stronger phenotypes than those caused by the elimination of aminoglycoside-inactivating enzymes. Second, the core functions mediating resistance were nearly identical in the wild type and a deletion mutant lacking a genome resistance island that encodes the inactivating enzymes. Thus, most or all of the core resistance determinants important in the absence of the enzymes are also important in their presence. Third, reductions in tobramycin resistance caused by different core mutations were additive, and highly sensitive double and triple mutants (with 250-fold reductions in the MIC) that retained accessory resistance genes could be constructed. Core processes that contribute most strongly to intrinsic tobramycin resistance include phospholipid biosynthesis, phosphate regulation, and envelope homeostasis. IMPORTANCE The inexorable increase in bacterial antibiotic resistance threatens to undermine many of the procedures that transformed medicine in the last century. One strategy to meet the challenge antibiotic resistance poses is the development of drugs that undermine resistance. To identify potential targets for such adjuvants, we identified the functions underlying resistance to an important class of antibiotics for one of the most highly resistant pathogens known.
format	article
author	Larry A. Gallagher Samuel A. Lee Colin Manoil
author_facet	Larry A. Gallagher Samuel A. Lee Colin Manoil
author_sort	Larry A. Gallagher
title	Importance of Core Genome Functions for an Extreme Antibiotic Resistance Trait
title_short	Importance of Core Genome Functions for an Extreme Antibiotic Resistance Trait
title_full	Importance of Core Genome Functions for an Extreme Antibiotic Resistance Trait
title_fullStr	Importance of Core Genome Functions for an Extreme Antibiotic Resistance Trait
title_full_unstemmed	Importance of Core Genome Functions for an Extreme Antibiotic Resistance Trait
title_sort	importance of core genome functions for an extreme antibiotic resistance trait
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/a451ed5ce73e44afafe67ad0c35c019e
work_keys_str_mv	AT larryagallagher importanceofcoregenomefunctionsforanextremeantibioticresistancetrait AT samuelalee importanceofcoregenomefunctionsforanextremeantibioticresistancetrait AT colinmanoil importanceofcoregenomefunctionsforanextremeantibioticresistancetrait
_version_	1718427293269884928

Importance of Core Genome Functions for an Extreme Antibiotic Resistance Trait

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