Insights into Acinetobacter baumannii fatty acid synthesis 3-oxoacyl-ACP reductases

Abstract Treatments for ‘superbug’ infections are the focus for innovative research, as drug resistance threatens human health and medical practices globally. In particular, Acinetobacter baumannii (Ab) infections are repeatedly reported as difficult to treat due to increasing antibiotic resistance....

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Emily M. Cross, Felise G. Adams, Jack K. Waters, David Aragão, Bart A. Eijkelkamp, Jade K. Forwood
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ae2ebd4988ec45ceb4dfc8bbb8a714a0
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ae2ebd4988ec45ceb4dfc8bbb8a714a0
record_format	dspace
spelling	oai:doaj.org-article:ae2ebd4988ec45ceb4dfc8bbb8a714a02021-12-02T14:25:32ZInsights into Acinetobacter baumannii fatty acid synthesis 3-oxoacyl-ACP reductases10.1038/s41598-021-86400-12045-2322https://doaj.org/article/ae2ebd4988ec45ceb4dfc8bbb8a714a02021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86400-1https://doaj.org/toc/2045-2322Abstract Treatments for ‘superbug’ infections are the focus for innovative research, as drug resistance threatens human health and medical practices globally. In particular, Acinetobacter baumannii (Ab) infections are repeatedly reported as difficult to treat due to increasing antibiotic resistance. Therefore, there is increasing need to identify novel targets in the development of different antimicrobials. Of particular interest is fatty acid synthesis, vital for the formation of phospholipids, lipopolysaccharides/lipooligosaccharides, and lipoproteins of Gram-negative envelopes. The bacterial type II fatty acid synthesis (FASII) pathway is an attractive target for the development of inhibitors and is particularly favourable due to the differences from mammalian type I fatty acid synthesis. Discrete enzymes in this pathway include two reductase enzymes: 3-oxoacyl-acyl carrier protein (ACP) reductase (FabG) and enoyl-ACP reductase (FabI). Here, we investigate annotated FabG homologs, finding a low-molecular weight 3-oxoacyl-ACP reductase, as the most likely FASII FabG candidate, and high-molecular weight 3-oxoacyl-ACP reductase (HMwFabG), showing differences in structure and coenzyme preference. To date, this is the second bacterial high-molecular weight FabG structurally characterized, following FabG4 from Mycobacterium. We show that ΔAbHMwfabG is impaired for growth in nutrient rich media and pellicle formation. We also modelled a third 3-oxoacyl-ACP reductase, which we annotated as AbSDR. Despite containing residues for catalysis and the ACP coordinating motif, biochemical analyses showed limited activity against an acetoacetyl-CoA substrate in vitro. Inhibitors designed to target FabG proteins and thus prevent fatty acid synthesis may provide a platform for use against multidrug-resistant pathogens including A. baumannii.Emily M. CrossFelise G. AdamsJack K. WatersDavid AragãoBart A. EijkelkampJade K. ForwoodNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Emily M. Cross Felise G. Adams Jack K. Waters David Aragão Bart A. Eijkelkamp Jade K. Forwood Insights into Acinetobacter baumannii fatty acid synthesis 3-oxoacyl-ACP reductases
description	Abstract Treatments for ‘superbug’ infections are the focus for innovative research, as drug resistance threatens human health and medical practices globally. In particular, Acinetobacter baumannii (Ab) infections are repeatedly reported as difficult to treat due to increasing antibiotic resistance. Therefore, there is increasing need to identify novel targets in the development of different antimicrobials. Of particular interest is fatty acid synthesis, vital for the formation of phospholipids, lipopolysaccharides/lipooligosaccharides, and lipoproteins of Gram-negative envelopes. The bacterial type II fatty acid synthesis (FASII) pathway is an attractive target for the development of inhibitors and is particularly favourable due to the differences from mammalian type I fatty acid synthesis. Discrete enzymes in this pathway include two reductase enzymes: 3-oxoacyl-acyl carrier protein (ACP) reductase (FabG) and enoyl-ACP reductase (FabI). Here, we investigate annotated FabG homologs, finding a low-molecular weight 3-oxoacyl-ACP reductase, as the most likely FASII FabG candidate, and high-molecular weight 3-oxoacyl-ACP reductase (HMwFabG), showing differences in structure and coenzyme preference. To date, this is the second bacterial high-molecular weight FabG structurally characterized, following FabG4 from Mycobacterium. We show that ΔAbHMwfabG is impaired for growth in nutrient rich media and pellicle formation. We also modelled a third 3-oxoacyl-ACP reductase, which we annotated as AbSDR. Despite containing residues for catalysis and the ACP coordinating motif, biochemical analyses showed limited activity against an acetoacetyl-CoA substrate in vitro. Inhibitors designed to target FabG proteins and thus prevent fatty acid synthesis may provide a platform for use against multidrug-resistant pathogens including A. baumannii.
format	article
author	Emily M. Cross Felise G. Adams Jack K. Waters David Aragão Bart A. Eijkelkamp Jade K. Forwood
author_facet	Emily M. Cross Felise G. Adams Jack K. Waters David Aragão Bart A. Eijkelkamp Jade K. Forwood
author_sort	Emily M. Cross
title	Insights into Acinetobacter baumannii fatty acid synthesis 3-oxoacyl-ACP reductases
title_short	Insights into Acinetobacter baumannii fatty acid synthesis 3-oxoacyl-ACP reductases
title_full	Insights into Acinetobacter baumannii fatty acid synthesis 3-oxoacyl-ACP reductases
title_fullStr	Insights into Acinetobacter baumannii fatty acid synthesis 3-oxoacyl-ACP reductases
title_full_unstemmed	Insights into Acinetobacter baumannii fatty acid synthesis 3-oxoacyl-ACP reductases
title_sort	insights into acinetobacter baumannii fatty acid synthesis 3-oxoacyl-acp reductases
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ae2ebd4988ec45ceb4dfc8bbb8a714a0
work_keys_str_mv	AT emilymcross insightsintoacinetobacterbaumanniifattyacidsynthesis3oxoacylacpreductases AT felisegadams insightsintoacinetobacterbaumanniifattyacidsynthesis3oxoacylacpreductases AT jackkwaters insightsintoacinetobacterbaumanniifattyacidsynthesis3oxoacylacpreductases AT davidaragao insightsintoacinetobacterbaumanniifattyacidsynthesis3oxoacylacpreductases AT bartaeijkelkamp insightsintoacinetobacterbaumanniifattyacidsynthesis3oxoacylacpreductases AT jadekforwood insightsintoacinetobacterbaumanniifattyacidsynthesis3oxoacylacpreductases
_version_	1718391389363896320

Insights into Acinetobacter baumannii fatty acid synthesis 3-oxoacyl-ACP reductases

Ejemplares similares