The Response Regulator BfmR Is a Potential Drug Target for Acinetobacter baumannii

Russo, Thomas A.; Manohar, Akshay; Beanan, Janet M.; Olson, Ruth; MacDonald, Ulrike; Graham, J.; Umland, Timothy C.

doi:10.1128/msphere.00082-16

Cited by 79 publications

(91 citation statements)

References 71 publications

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“…A study made by Russo et al . () revealed that the bfmR mutant decreased the A. baumannii survival in human serum. In addition, BfmR controls EPS production, pilus assembly system, cell attachment and biofilm formation (Thompson et al .…”

Section: Discussionmentioning

confidence: 98%

“…BfmR is the response regulator of a two-component signal transduction system, which transmits the signal from the sensor histidine kinase (BfmS) and acts as a transcriptional regulator. A study made by Russo et al (2016) revealed that the bfmR mutant decreased the A. baumannii survival in human serum. In addition, BfmR controls EPS production, pilus assembly system, cell attachment and biofilm formation (Thompson et al 2012).…”

Section: Discussionmentioning

confidence: 99%

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Biofilm inhibitory efficiency of phytol in combination with cefotaxime against nosocomial pathogen Acinetobacter baumannii

et al. 2018

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Biofilm inhibitory efficiency of phytol in combination with cefotaxime against nosocomial pathogen Acinetobacter baumannii

et al. 2018

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“…Importantly, the genes identified as essential in vivo overlapped poorly with genes that were previously identified as essential in other Gram negative species under laboratory conditions, and none of them are targeted by clinically used antibiotics or antimicrobial molecules that are currently being developed. In a later study, the same authors validated one of the essential genes identified in this study, the gene encoding the response regulator BfmR, as a potential target for the development of novel antibiotics [51]. …”

Section: Essential Genes As Targets For Antibiotic Discoverymentioning

confidence: 99%

Using bacterial genomes and essential genes for the development of new antibiotics

Fields

Lee

McConnell

2017

Biochemical Pharmacology

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The shrinking antibiotic development pipeline together with the global increase in antibiotic resistant infections requires that new molecules with antimicrobial activity are developed. Traditional empirical screening approaches of natural and non-natural compounds have identified the majority of antibiotics that are currently available, however this approach has produced relatively few new antibiotics over the last few decades. The vast amount of bacterial genome sequence information that has become available since the sequencing of the first bacterial genome more than 20 years ago holds potential for contributing to the discovery of novel antimicrobial compounds. Comparative genomic approaches can identify genes that are highly conserved within and between bacterial species, and thus may represent genes that participate in key bacterial processes. Whole genome mutagenesis studies can also identify genes necessary for bacterial growth and survival under different environmental conditions, making them attractive targets for the development of novel inhibitory compounds. In addition, transcriptomic and proteomic approaches can be used to characterize RNA and protein levels on a cellular scale, providing information on bacterial physiology that can be applied to antibiotic target identification. Finally, bacterial genomes can be mined to identify biosynthetic pathways that produce many intrinsic antimicrobial compounds and peptides. In this review, we provide an overview of past and current efforts aimed at using bacterial genomic data in the discovery and development of novel antibiotics.

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“…It is also known that genes encoding Bap protein and efflux pumps are important for biofilms (Brossard and Campagnari, 2012;He et al, 2015;Loehfelm et al, 2008;Tomaras et al, 2008Tomaras et al, , 2003. The BfmR response regulator is part of a two-component system (BfmRS) (Farrow et al, 2018;Geisinger and Isberg, 2015;Russo et al, 2016;Tomaras et al, 2008;Wang et al, 2014) that results in BfmR phosphorylation. It is unknown if bfmR expression is induced by another factor or whether de-repression by phosphorylated BfmR, with lower affinity for its operator site (Draughn et al, 2018), is enough for induction.…”

Section: Introductionmentioning

confidence: 99%

RecA levels modulate biofilm development inAcinetobacter baumannii

Ching

Muller

Brychcy

et al. 2019

Preprint

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9Acinetobacter baumannii, a Gram-negative opportunistic pathogen, is a leading cause of hospital-10 acquired infections. A. baumannii is difficult to eradicate from hospitals due to its propensity to 11 quickly gain antibiotic resistances and ability to robustly survive on dry surfaces. These strategies are 12 largely mediated by mutagenesis and biofilm development, respectively. Mutagenesis is partly 13 governed by the DNA damage response (DDR). Biofilms are multicellular communities, often 14 surface-attached, that are more difficult to eradicate than free-living planktonic cells. There is 15 increasing evidence that the DDR and biofilm development are linked processes. Here, we show that 16 upon DNA damage, the relative intracellular concentration of RecA, the key DDR protein, is lower 17 than those of Escherichia coli. Notably, we report that RecA negatively influences biofilm 18 development. Cells lacking RecA (∆recA), that are unable to upregulate the DDR, have increased 19 surface attachment and sugar content within the biofilm matrix. We further show that in A. 20 baumannii, a modest increase in RecA concentrations, akin to DDR induction, decreases surface-21 attachment. Importantly, biofilms formed by ∆ recA cells are more difficult to eradicate with 22 2 antibiotic treatment. The evidence suggests that the A. baumannii DDR influences survival 23 independent from mutagenesis. It also demonstrates the importance of understanding fundamental 24 biology to better appreciate the relationships between different bacterial survival strategies. 25 Introduction 26Acinetobacter baumannii is an emerging Gram-negative opportunistic pathogen and one of the 27 ESKAPE pathogens, a group of bacteria responsible for the majority of hospital-acquired infections 28 1 . Interest in these bacteria has stemmed from A. baumannii outbreaks in hospitals worldwide that are 29 difficult to eradicate, due to increased multi-drug resistance (MDR) 2 and resistance to desiccation 3 . 30A. baumannii is very dangerous to immunocompromised individuals, causing different illnesses, 31including pneumonia, septicemia, and wound infections 4 . 32One response pathway that underlies MDR is the DNA damage response (DDR). When gene 33 products involved in antibiotic binding or processing are mutated, resistance is acquired 5 . 34Mutagenesis can result from induction of error-prone DNA polymerase genes which are part of the 35 DDR regulon, a strategy used by different bacteria 6,7 . In Escherichia coli and many other bacteria, 36 the cells' main recombinase, RecA, and the global transcriptional repressor, LexA, manage the DDR, 37 also known as the SOS response 8 . In A. baumannii, however, there is no known LexA homologue, 38 making the A. baumannii DDR circuitry unique 9,10 . We have shown that in A. baumannii expression 39 of multiple error-prone polymerases and clinically-relevant antibiotic resistance acquisition are 40 dependent on RecA 11 . 41A. baumannii is notorious for its ability to robustly survive on surfaces. Under dry conditions, A....

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The Response Regulator BfmR Is a Potential Drug Target for Acinetobacter baumannii

Cited by 79 publications

References 71 publications

Biofilm inhibitory efficiency of phytol in combination with cefotaxime against nosocomial pathogen Acinetobacter baumannii

Biofilm inhibitory efficiency of phytol in combination with cefotaxime against nosocomial pathogen Acinetobacter baumannii

Using bacterial genomes and essential genes for the development of new antibiotics

RecA levels modulate biofilm development inAcinetobacter baumannii

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