Aminoglycoside Heteroresistance in <named-content content-type="genus-species">Acinetobacter baumannii</named-content> AB5075

ABSTRACT Heteroresistance is a phenomenon where a subpopulation of cells exhibits higher levels of antibiotic resistance than the general population. Analysis of tobramycin resistance in Acinetobacter baumannii AB5075 using Etest strips demonstrated that colonies with increased resistance arose at h...

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Autores principales:	Sarah E. Anderson, Edgar X. Sherman, David S. Weiss, Philip N. Rather
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Acinetobacter baumannii aminoglycoside-modifying enzymes gene amplification heteroresistance Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c1fd3a64d29540738bd97d918137ec35
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spelling	oai:doaj.org-article:c1fd3a64d29540738bd97d918137ec352021-11-15T15:25:50ZAminoglycoside Heteroresistance in <named-content content-type="genus-species">Acinetobacter baumannii</named-content> AB507510.1128/mSphere.00271-182379-5042https://doaj.org/article/c1fd3a64d29540738bd97d918137ec352018-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00271-18https://doaj.org/toc/2379-5042ABSTRACT Heteroresistance is a phenomenon where a subpopulation of cells exhibits higher levels of antibiotic resistance than the general population. Analysis of tobramycin resistance in Acinetobacter baumannii AB5075 using Etest strips demonstrated that colonies with increased resistance arose at high frequency within the zone of growth inhibition. The presence of a resistant subpopulation was confirmed by population analysis profiling (PAP). The tobramycin-resistant subpopulation was cross resistant to gentamicin but not amikacin. The increased tobramycin resistance phenotype was highly unstable, and cells reverted to a less resistant population at frequencies of 60 to 90% after growth on nonselective media. Furthermore, the frequency of the resistant subpopulation was not increased by preincubation with subinhibitory concentrations of tobramycin. The tobramycin-resistant subpopulation was shown to replicate during the course of antibiotic treatment, demonstrating that these were not persister cells. In A. baumannii AB5075, a large plasmid (p1AB5075) carries aadB, a 2″-nucleotidyltransferase that confers resistance to both tobramycin and gentamicin but not amikacin. The aadB gene is part of an integron and is carried adjacent to four additional resistance genes that are all flanked by copies of an integrase gene. In isolates with increased resistance, this region was highly amplified in a RecA-dependent manner. However, in a recA mutant, colonies with unstable tobramycin resistance arose by a mechanism that did not involve amplification of this region. These data indicate that tobramycin heteroresistance occurs by at least two mechanisms in A. baumannii, and future studies to determine its effect on patient outcomes are warranted. IMPORTANCE Acinetobacter baumannii has become an important pathogen in hospitals worldwide, where the incidence of these infections has been increasing. A. baumannii infections have become exceedingly difficult to treat due to a rapid increase in the frequency of multidrug- and pan-resistant isolates. This has prompted the World Health Organization to list A. baumannii as the top priority for the research and development of new antibiotics. This study reports for the first time a detailed analysis of aminoglycoside heteroresistance in A. baumannii. We define the mechanistic basis for heteroresistance, where the aadB(ant2″)Ia gene encoding an aminoglycoside adenylyltransferase becomes highly amplified in a RecA-dependent manner. Remarkably, this amplification of 20 to 40 copies occurs stochastically in 1/200 cells in the absence of antibiotic selection. In addition, we provide evidence for a second RecA-independent mechanism for aminoglycoside heteroresistance. This study reveals that aminoglycoside resistance in A. baumannii is far more complex than previously realized and has important implications for the use of aminoglycosides in treating A. baumannii infections.Sarah E. AndersonEdgar X. ShermanDavid S. WeissPhilip N. RatherAmerican Society for MicrobiologyarticleAcinetobacter baumanniiaminoglycoside-modifying enzymesgene amplificationheteroresistanceMicrobiologyQR1-502ENmSphere, Vol 3, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Acinetobacter baumannii aminoglycoside-modifying enzymes gene amplification heteroresistance Microbiology QR1-502
spellingShingle	Acinetobacter baumannii aminoglycoside-modifying enzymes gene amplification heteroresistance Microbiology QR1-502 Sarah E. Anderson Edgar X. Sherman David S. Weiss Philip N. Rather Aminoglycoside Heteroresistance in <named-content content-type="genus-species">Acinetobacter baumannii</named-content> AB5075
description	ABSTRACT Heteroresistance is a phenomenon where a subpopulation of cells exhibits higher levels of antibiotic resistance than the general population. Analysis of tobramycin resistance in Acinetobacter baumannii AB5075 using Etest strips demonstrated that colonies with increased resistance arose at high frequency within the zone of growth inhibition. The presence of a resistant subpopulation was confirmed by population analysis profiling (PAP). The tobramycin-resistant subpopulation was cross resistant to gentamicin but not amikacin. The increased tobramycin resistance phenotype was highly unstable, and cells reverted to a less resistant population at frequencies of 60 to 90% after growth on nonselective media. Furthermore, the frequency of the resistant subpopulation was not increased by preincubation with subinhibitory concentrations of tobramycin. The tobramycin-resistant subpopulation was shown to replicate during the course of antibiotic treatment, demonstrating that these were not persister cells. In A. baumannii AB5075, a large plasmid (p1AB5075) carries aadB, a 2″-nucleotidyltransferase that confers resistance to both tobramycin and gentamicin but not amikacin. The aadB gene is part of an integron and is carried adjacent to four additional resistance genes that are all flanked by copies of an integrase gene. In isolates with increased resistance, this region was highly amplified in a RecA-dependent manner. However, in a recA mutant, colonies with unstable tobramycin resistance arose by a mechanism that did not involve amplification of this region. These data indicate that tobramycin heteroresistance occurs by at least two mechanisms in A. baumannii, and future studies to determine its effect on patient outcomes are warranted. IMPORTANCE Acinetobacter baumannii has become an important pathogen in hospitals worldwide, where the incidence of these infections has been increasing. A. baumannii infections have become exceedingly difficult to treat due to a rapid increase in the frequency of multidrug- and pan-resistant isolates. This has prompted the World Health Organization to list A. baumannii as the top priority for the research and development of new antibiotics. This study reports for the first time a detailed analysis of aminoglycoside heteroresistance in A. baumannii. We define the mechanistic basis for heteroresistance, where the aadB(ant2″)Ia gene encoding an aminoglycoside adenylyltransferase becomes highly amplified in a RecA-dependent manner. Remarkably, this amplification of 20 to 40 copies occurs stochastically in 1/200 cells in the absence of antibiotic selection. In addition, we provide evidence for a second RecA-independent mechanism for aminoglycoside heteroresistance. This study reveals that aminoglycoside resistance in A. baumannii is far more complex than previously realized and has important implications for the use of aminoglycosides in treating A. baumannii infections.
format	article
author	Sarah E. Anderson Edgar X. Sherman David S. Weiss Philip N. Rather
author_facet	Sarah E. Anderson Edgar X. Sherman David S. Weiss Philip N. Rather
author_sort	Sarah E. Anderson
title	Aminoglycoside Heteroresistance in <named-content content-type="genus-species">Acinetobacter baumannii</named-content> AB5075
title_short	Aminoglycoside Heteroresistance in <named-content content-type="genus-species">Acinetobacter baumannii</named-content> AB5075
title_full	Aminoglycoside Heteroresistance in <named-content content-type="genus-species">Acinetobacter baumannii</named-content> AB5075
title_fullStr	Aminoglycoside Heteroresistance in <named-content content-type="genus-species">Acinetobacter baumannii</named-content> AB5075
title_full_unstemmed	Aminoglycoside Heteroresistance in <named-content content-type="genus-species">Acinetobacter baumannii</named-content> AB5075
title_sort	aminoglycoside heteroresistance in <named-content content-type="genus-species">acinetobacter baumannii</named-content> ab5075
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/c1fd3a64d29540738bd97d918137ec35
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Aminoglycoside Heteroresistance in <named-content content-type="genus-species">Acinetobacter baumannii</named-content> AB5075

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