Cargando…

Rifabutin Suppresses Inducible Clarithromycin Resistance in Mycobacterium abscessus by Blocking Induction of whiB7 and erm41

Clarithromycin (CLR) is the corner stone in regimens for the treatment of lung disease caused by Mycobacterium abscessus (Mab). However, many strains harbor the CLR-inducible CLR resistance gene erm41, encoding a ribosome methylase. Induction of erm41 is mediated by the transcription factor whiB7. W...

Descripción completa

Detalles Bibliográficos
Autores principales: Aziz, Dinah Binte, Go, Mei Lin, Dick, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168051/
https://www.ncbi.nlm.nih.gov/pubmed/32050554
http://dx.doi.org/10.3390/antibiotics9020072
_version_ 1783523612845670400
author Aziz, Dinah Binte
Go, Mei Lin
Dick, Thomas
author_facet Aziz, Dinah Binte
Go, Mei Lin
Dick, Thomas
author_sort Aziz, Dinah Binte
collection PubMed
description Clarithromycin (CLR) is the corner stone in regimens for the treatment of lung disease caused by Mycobacterium abscessus (Mab). However, many strains harbor the CLR-inducible CLR resistance gene erm41, encoding a ribosome methylase. Induction of erm41 is mediated by the transcription factor whiB7. We hypothesized that an inhibitor of RNA synthesis should be able to block the whiB7–erm41 induction response to CLR exposure and thus suppress CLR resistance. Recently, we discovered that the rifampicin analog rifabutin (RFB) shows attractive potency against Mab. To determine whether RFB-CLR combinations are synergistic, a checkerboard analysis against a collection of erm41 positive and negative Mab strains was carried out. This revealed synergy of the two drugs for erm41 positive but not for erm41 negative strains. To determine whether RFB’s potentiation effect was due to inhibition of the transcriptional induction of the whiB7–erm41 resistance system, we measured the effect of CLR alone and in combination with RFB on whiB7 and erm41 mRNA levels. CLR alone strongly induced whiB7 and erm41 expression as expected. The synergistic, growth-inhibiting combination of RFB with CLR blocked induction of both genes. These results suggest that RFB suppresses inducible CLR resistance by preventing induction of whiB7 and erm41 expression.
format Online
Article
Text
id pubmed-7168051
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-71680512020-04-21 Rifabutin Suppresses Inducible Clarithromycin Resistance in Mycobacterium abscessus by Blocking Induction of whiB7 and erm41 Aziz, Dinah Binte Go, Mei Lin Dick, Thomas Antibiotics (Basel) Article Clarithromycin (CLR) is the corner stone in regimens for the treatment of lung disease caused by Mycobacterium abscessus (Mab). However, many strains harbor the CLR-inducible CLR resistance gene erm41, encoding a ribosome methylase. Induction of erm41 is mediated by the transcription factor whiB7. We hypothesized that an inhibitor of RNA synthesis should be able to block the whiB7–erm41 induction response to CLR exposure and thus suppress CLR resistance. Recently, we discovered that the rifampicin analog rifabutin (RFB) shows attractive potency against Mab. To determine whether RFB-CLR combinations are synergistic, a checkerboard analysis against a collection of erm41 positive and negative Mab strains was carried out. This revealed synergy of the two drugs for erm41 positive but not for erm41 negative strains. To determine whether RFB’s potentiation effect was due to inhibition of the transcriptional induction of the whiB7–erm41 resistance system, we measured the effect of CLR alone and in combination with RFB on whiB7 and erm41 mRNA levels. CLR alone strongly induced whiB7 and erm41 expression as expected. The synergistic, growth-inhibiting combination of RFB with CLR blocked induction of both genes. These results suggest that RFB suppresses inducible CLR resistance by preventing induction of whiB7 and erm41 expression. MDPI 2020-02-10 /pmc/articles/PMC7168051/ /pubmed/32050554 http://dx.doi.org/10.3390/antibiotics9020072 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Aziz, Dinah Binte
Go, Mei Lin
Dick, Thomas
Rifabutin Suppresses Inducible Clarithromycin Resistance in Mycobacterium abscessus by Blocking Induction of whiB7 and erm41
title Rifabutin Suppresses Inducible Clarithromycin Resistance in Mycobacterium abscessus by Blocking Induction of whiB7 and erm41
title_full Rifabutin Suppresses Inducible Clarithromycin Resistance in Mycobacterium abscessus by Blocking Induction of whiB7 and erm41
title_fullStr Rifabutin Suppresses Inducible Clarithromycin Resistance in Mycobacterium abscessus by Blocking Induction of whiB7 and erm41
title_full_unstemmed Rifabutin Suppresses Inducible Clarithromycin Resistance in Mycobacterium abscessus by Blocking Induction of whiB7 and erm41
title_short Rifabutin Suppresses Inducible Clarithromycin Resistance in Mycobacterium abscessus by Blocking Induction of whiB7 and erm41
title_sort rifabutin suppresses inducible clarithromycin resistance in mycobacterium abscessus by blocking induction of whib7 and erm41
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168051/
https://www.ncbi.nlm.nih.gov/pubmed/32050554
http://dx.doi.org/10.3390/antibiotics9020072
work_keys_str_mv AT azizdinahbinte rifabutinsuppressesinducibleclarithromycinresistanceinmycobacteriumabscessusbyblockinginductionofwhib7anderm41
AT gomeilin rifabutinsuppressesinducibleclarithromycinresistanceinmycobacteriumabscessusbyblockinginductionofwhib7anderm41
AT dickthomas rifabutinsuppressesinducibleclarithromycinresistanceinmycobacteriumabscessusbyblockinginductionofwhib7anderm41