A Sensory Complex Consisting of an ATP-binding Cassette Transporter and a Two-component Regulatory System Controls Bacitracin Resistance in Bacillus subtilis

Dintner, Sebastian; Heermann, Ralf; Fang, Chong; Jung, Kirsten; Gebhard, Susanne

doi:10.1074/jbc.m114.596221

Cited by 74 publications

(103 citation statements)

References 46 publications

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“…We performed whole genome sequencing of the DAP‐R derivatives in both strain backgrounds in order to identify genetic changes associated with development of DAP‐R (Table ). Interestingly, both strains developed mutations in the sensing module of the two‐component regulatory system YxdJK, a BceAB‐like system previously linked to bacitracin (BAC) resistance in Bacillus subtilis and E. faecalis and chlorhexidine tolerance in E. faecium (Dintner et al , ; Gebhard et al , ; Prieto et al , ). The YxdJK system encodes a sensor histidine kinase ( yxdK ) and cognate response regulator ( yxdJ ), which positively regulates a putative ABC transporter (YvcRS, required for signal transduction along with YxdK) and a second transporter (YxdLM) responsible for the BAC resistance phenotype (Gebhard et al , ).…”

Section: Resultsmentioning

confidence: 99%

LiaR‐independent pathways to daptomycin resistance in Enterococcus faecalis reveal a multilayer defense against cell envelope antibiotics

Miller

Tran

Diaz

et al. 2019

Molecular Microbiology

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Summary The lipopeptide antibiotic daptomycin (DAP) is a key drug against serious enterococcal infections, but the emergence of resistance in the clinical setting is a major concern. The LiaFSR system plays a prominent role in the development of DAP resistance (DAP‐R) in enterococci, and blocking this stress response system has been proposed as a novel therapeutic strategy. In this work, we identify LiaR‐independent pathways in Enterococcus faecalis that regulate cell membrane adaptation in response to antibiotics. We adapted E. faecalis OG1RF (a laboratory strain) and S613TM (a clinical strain) lacking liaR to increasing concentrations of DAP, leading to the development of DAP‐R and elevated MICs to bacitracin and ceftriaxone. Whole genome sequencing identified changes in the YxdJK two‐component regulatory system and a putative fatty acid kinase (dak) in both DAP‐R strains. Deletion of the gene encoding the YxdJ response regulator in both the DAP‐R mutant and wild‐type OG1RF decreased MICs to DAP, even when a functional LiaFSR system was present. Mutations in dak were associated with slower growth, decreased membrane fluidity and alterations of cell morphology. These findings suggest that overlapping stress response pathways can provide protection against antimicrobial peptides in E. faecalis at a significant cost in bacterial fitness.

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Section: Resultsmentioning

confidence: 99%

LiaR‐independent pathways to daptomycin resistance in Enterococcus faecalis reveal a multilayer defense against cell envelope antibiotics

Miller

Tran

Diaz

et al. 2019

Molecular Microbiology

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“…High-level glutamate transporter operon expression may provide MT45 with more glutamate for the efficient synthesis of surfactin. More importantly, ABC transporters together with the neighbouring TCS have been recognized as detoxification systems for resistance against antimicrobial peptides in many Firmicutes bacteria3839. Surfactin works as an antibiotic by attacking the bacterial cell membrane9.…”

Section: Resultsmentioning

confidence: 99%

Genome and transcriptome analysis of surfactin biosynthesis in Bacillus amyloliquefaciens MT45

Zhi

2017

Sci Rep

106

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Natural Bacillus isolates generate limited amounts of surfactin (<10% of their biomass), which functions as an antibiotic or signalling molecule in inter-/intra-specific interactions. However, overproduction of surfactin in Bacillus amyloliquefaciens MT45 was observed at a titre of 2.93 g/l, which is equivalent to half of the maximum biomass. To systemically unravel this efficient biosynthetic process, the genome and transcriptome of this bacterium were compared with those of B. amyloliquefaciens type strain DSM7T. MT45 possesses a smaller genome while containing more unique transporters and resistance-associated genes. Comparative transcriptome analysis revealed notable enrichment of the surfactin synthesis pathway in MT45, including central carbon metabolism and fatty acid biosynthesis to provide sufficient quantities of building precursors. Most importantly, the modular surfactin synthase overexpressed (9 to 49-fold) in MT45 compared to DSM7T suggested efficient surfactin assembly and resulted in the overproduction of surfactin. Furthermore, based on the expression trends observed in the transcriptome, there are multiple potential regulatory genes mediating the expression of surfactin synthase. Thus, the results of the present study provide new insights regarding the synthesis and regulation of surfactin in high-producing strain and enrich the genomic and transcriptomic resources available for B. amyloliquefaciens.

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“…Initial evidence from cell wall-less L-forms of B. subtilis showed that the Bce system is triggered in the absence of cell wall biosynthesis (Wolf et al 2012), arguing for a 'drug-sensing' mechanism of stimulus perception. This view was supported by in vitro results indicating that BceB is able to bind bacitracin directly (Dintner et al 2014). In vivo results, on the other hand, argued for BceB binding UPP and even suggested that this transporter might play a role as a UPP flippase of the cycle (Kingston et al 2014).…”

Section: Drug Sensing Versus Target Sensingmentioning

confidence: 92%

“…Moreover, a single point mutation in the Walker B motif of the ATPase BceA (exhibiting a highly reduced rate of ATP hydrolysis) also abolished signaling via BceRS, showing that ATP hydrolysis, and thus active transport of bacitracin, is required for stimulus perception (Rietkötter et al 2008). Bacterial two-hybrid analyses together with in vitro pulldown assays further showed that the permease BceB forms a complex with the histidine kinase BceS (Dintner et al 2014) (Fig. 3a), and amino acid residues crucial for this contact have been identified in the permease BceB (Kallenberg et al 2013).…”

Section: The Bcers-bceab Complex Acts As An Antibiotic Flux Sensormentioning

confidence: 95%

The cell envelope stress response of Bacillus subtilis: from static signaling devices to dynamic regulatory network

2016

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The cell envelope stress response (CESR) encompasses all regulatory events that enable a cell to protect the integrity of its envelope, an essential structure of any bacterial cell. The underlying signaling network is particularly well understood in the Gram-positive model organism Bacillus subtilis. It consists of a number of two-component systems (2CS) and extracytoplasmic function σ factors that together regulate the production of both specific resistance determinants and general mechanisms to protect the envelope against antimicrobial peptides targeting the biogenesis of the cell wall. Here, we summarize the current picture of the B. subtilis CESR network, from the initial identification of the corresponding signaling devices to unraveling their interdependence and the underlying regulatory hierarchy within the network. In the course of detailed mechanistic studies, a number of novel signaling features could be described for the 2CSs involved in mediating CESR. This includes a novel class of so-called intramembrane-sensing histidine kinases (IM-HKs), which-instead of acting as stress sensors themselves-are activated via interprotein signal transfer. Some of these IM-HKs are involved in sensing the flux of antibiotic resistance transporters, a unique mechanism of responding to extracellular antibiotic challenge.

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A Sensory Complex Consisting of an ATP-binding Cassette Transporter and a Two-component Regulatory System Controls Bacitracin Resistance in Bacillus subtilis

Cited by 74 publications

References 46 publications

LiaR‐independent pathways to daptomycin resistance in Enterococcus faecalis reveal a multilayer defense against cell envelope antibiotics

LiaR‐independent pathways to daptomycin resistance in Enterococcus faecalis reveal a multilayer defense against cell envelope antibiotics

Genome and transcriptome analysis of surfactin biosynthesis in Bacillus amyloliquefaciens MT45

The cell envelope stress response of Bacillus subtilis: from static signaling devices to dynamic regulatory network

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