A Nutrient-limited Screen Unmasks Rifabutin Hyperactivity for XDR Acinetobacter baumannii

Industry screens of large chemical libraries traditionally have relied on rich media to ensure rapid bacterial growth in high-throughput testing. We used eukaryotic, nutrient-limited growth media in a compound screen that unmasked a previously unknown hyper-activity of the old antibiotic, rifabutin...

Descripción completa

Detalles Bibliográficos
Autores principales: Luna, B., Trebosc, V., Lee, B., Bakowski, M., Ulhaq, A., Yan, J., Lu, P., Cheng, J., Nielsen, T., Lim, J., Ketphan, W., Eoh, H., McNamara, C., Skandalis, N., She, R., Kemmer, C., Lociuro, S., Dale, G. E., Spellberg, B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483275/
https://www.ncbi.nlm.nih.gov/pubmed/32514072
http://dx.doi.org/10.1038/s41564-020-0737-6
_version_ 1783580911210594304
author Luna, B.
Trebosc, V.
Lee, B.
Bakowski, M.
Ulhaq, A.
Yan, J.
Lu, P.
Cheng, J.
Nielsen, T.
Lim, J.
Ketphan, W.
Eoh, H.
McNamara, C.
Skandalis, N.
She, R.
Kemmer, C.
Lociuro, S.
Dale, G. E.
Spellberg, B.
author_facet Luna, B.
Trebosc, V.
Lee, B.
Bakowski, M.
Ulhaq, A.
Yan, J.
Lu, P.
Cheng, J.
Nielsen, T.
Lim, J.
Ketphan, W.
Eoh, H.
McNamara, C.
Skandalis, N.
She, R.
Kemmer, C.
Lociuro, S.
Dale, G. E.
Spellberg, B.
author_sort Luna, B.
collection PubMed
description Industry screens of large chemical libraries traditionally have relied on rich media to ensure rapid bacterial growth in high-throughput testing. We used eukaryotic, nutrient-limited growth media in a compound screen that unmasked a previously unknown hyper-activity of the old antibiotic, rifabutin (RBT), against highly resistant Acinetobacter baumannii. In nutrient-limited, but not rich media, RBT was 200-fold more potent than rifampin (RIF). RBT was also substantially more effective in vivo. The mechanism of enhanced efficacy was a Trojan horse-like import of RBT but not RIF through FhuE, only in nutrient-limited conditions. These results are of fundamental importance to efforts to discover antibacterial agents.
format Online
Article
Text
id pubmed-7483275
institution National Center for Biotechnology Information
language English
publishDate 2020
record_format MEDLINE/PubMed
spelling pubmed-74832752020-12-08 A Nutrient-limited Screen Unmasks Rifabutin Hyperactivity for XDR Acinetobacter baumannii Luna, B. Trebosc, V. Lee, B. Bakowski, M. Ulhaq, A. Yan, J. Lu, P. Cheng, J. Nielsen, T. Lim, J. Ketphan, W. Eoh, H. McNamara, C. Skandalis, N. She, R. Kemmer, C. Lociuro, S. Dale, G. E. Spellberg, B. Nat Microbiol Article Industry screens of large chemical libraries traditionally have relied on rich media to ensure rapid bacterial growth in high-throughput testing. We used eukaryotic, nutrient-limited growth media in a compound screen that unmasked a previously unknown hyper-activity of the old antibiotic, rifabutin (RBT), against highly resistant Acinetobacter baumannii. In nutrient-limited, but not rich media, RBT was 200-fold more potent than rifampin (RIF). RBT was also substantially more effective in vivo. The mechanism of enhanced efficacy was a Trojan horse-like import of RBT but not RIF through FhuE, only in nutrient-limited conditions. These results are of fundamental importance to efforts to discover antibacterial agents. 2020-06-08 2020-09 /pmc/articles/PMC7483275/ /pubmed/32514072 http://dx.doi.org/10.1038/s41564-020-0737-6 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Luna, B.
Trebosc, V.
Lee, B.
Bakowski, M.
Ulhaq, A.
Yan, J.
Lu, P.
Cheng, J.
Nielsen, T.
Lim, J.
Ketphan, W.
Eoh, H.
McNamara, C.
Skandalis, N.
She, R.
Kemmer, C.
Lociuro, S.
Dale, G. E.
Spellberg, B.
A Nutrient-limited Screen Unmasks Rifabutin Hyperactivity for XDR Acinetobacter baumannii
title A Nutrient-limited Screen Unmasks Rifabutin Hyperactivity for XDR Acinetobacter baumannii
title_full A Nutrient-limited Screen Unmasks Rifabutin Hyperactivity for XDR Acinetobacter baumannii
title_fullStr A Nutrient-limited Screen Unmasks Rifabutin Hyperactivity for XDR Acinetobacter baumannii
title_full_unstemmed A Nutrient-limited Screen Unmasks Rifabutin Hyperactivity for XDR Acinetobacter baumannii
title_short A Nutrient-limited Screen Unmasks Rifabutin Hyperactivity for XDR Acinetobacter baumannii
title_sort nutrient-limited screen unmasks rifabutin hyperactivity for xdr acinetobacter baumannii
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483275/
https://www.ncbi.nlm.nih.gov/pubmed/32514072
http://dx.doi.org/10.1038/s41564-020-0737-6
work_keys_str_mv AT lunab anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT treboscv anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT leeb anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT bakowskim anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT ulhaqa anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT yanj anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT lup anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT chengj anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT nielsent anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT limj anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT ketphanw anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT eohh anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT mcnamarac anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT skandalisn anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT sher anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT kemmerc anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT lociuros anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT dalege anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT spellbergb anutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT lunab nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT treboscv nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT leeb nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT bakowskim nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT ulhaqa nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT yanj nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT lup nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT chengj nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT nielsent nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT limj nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT ketphanw nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT eohh nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT mcnamarac nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT skandalisn nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT sher nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT kemmerc nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT lociuros nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT dalege nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii
AT spellbergb nutrientlimitedscreenunmasksrifabutinhyperactivityforxdracinetobacterbaumannii

Ejemplares similares