Inhibition of the <scp>D</scp>‐alanine:<scp>D</scp>‐alanyl carrier protein ligase from <i>Bacillus subtilis</i> increases the bacterium's susceptibility to antibiotics that target the cell wall

May, Juergen; Finking, Robert; Wiegeshoff, Frank; Weber, Thomas; Bandur, Nina G.; Koert, Ulrich; Marahiel, Mohamed A.

doi:10.1111/j.1742-4658.2005.04700.x

Cited by 95 publications

(99 citation statements)

References 46 publications

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“…9). Related aminoacyl sulfamoyl adenosines were shown in previous studies to act as potent inhibitors of NRPS and non-NRPS A domains (94,210). The in vitro and in-culture inhibition efficacy of SAL-AMS was confirmed in further studies (215,303,304,324).…”

Section: Siderophore Pathway Inhibitorsmentioning

confidence: 60%

Siderophore-Based Iron Acquisition and Pathogen Control

Miethke

Marahiel

2007

Microbiol Mol Biol Rev

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1,440

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SUMMARY High-affinity iron acquisition is mediated by siderophore-dependent pathways in the majority of pathogenic and nonpathogenic bacteria and fungi. Considerable progress has been made in characterizing and understanding mechanisms of siderophore synthesis, secretion, iron scavenging, and siderophore-delivered iron uptake and its release. The regulation of siderophore pathways reveals multilayer networks at the transcriptional and posttranscriptional levels. Due to the key role of many siderophores during virulence, coevolution led to sophisticated strategies of siderophore neutralization by mammals and (re)utilization by bacterial pathogens. Surprisingly, hosts also developed essential siderophore-based iron delivery and cell conversion pathways, which are of interest for diagnostic and therapeutic studies. In the last decades, natural and synthetic compounds have gained attention as potential therapeutics for iron-dependent treatment of infections and further diseases. Promising results for pathogen inhibition were obtained with various siderophore-antibiotic conjugates acting as “Trojan horse” toxins and siderophore pathway inhibitors. In this article, general aspects of siderophore-mediated iron acquisition, recent findings regarding iron-related pathogen-host interactions, and current strategies for iron-dependent pathogen control will be reviewed. Further concepts including the inhibition of novel siderophore pathway targets are discussed.

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Section: Siderophore Pathway Inhibitorsmentioning

confidence: 60%

Siderophore-Based Iron Acquisition and Pathogen Control

Miethke

Marahiel

2007

Microbiol Mol Biol Rev

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1,440

1,302

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“…Our studies required knowing the genes that encode the tailoring enzymes. The genes involved in D-alanylation and α-O-GlcNAcylation were previously identified, but the gene encoding the transferase that attaches β-O-GlcNAc residues to WTAs was not (19)(20)(21)(22)(23). Here we report the identification of this unique gene, tarS, and we profile the substrate preferences of the encoded β-O-GlcNAc transferase.…”

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confidence: 99%

Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids

Brown

Xia

Luhachack

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

256

295

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Staphylococcus aureus peptidoglycan (PG) is densely functionalized with anionic polymers called wall teichoic acids (WTAs). These polymers contain three tailoring modifications: d -alanylation, α- O -GlcNAcylation, and β- O -GlcNAcylation. Here we describe the discovery and biochemical characterization of a unique glycosyltransferase, TarS, that attaches β- O -GlcNAc (β- O - N -acetyl- d -glucosamine) residues to S. aureus WTAs. We report that methicillin resistant S. aureus (MRSA) is sensitized to β-lactams upon tarS deletion. Unlike strains completely lacking WTAs, which are also sensitive to β-lactams, Δ tarS strains have no growth or cell division defects. Because neither α- O -GlcNAc nor β- O -Glucose modifications can confer resistance, the resistance phenotype requires a highly specific chemical modification of the WTA backbone, β- O -GlcNAc residues. These data suggest β- O -GlcNAcylated WTAs scaffold factors required for MRSA resistance. The β- O -GlcNAc transferase identified here, TarS, is a unique target for antimicrobials that sensitize MRSA to β-lactams.

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“…For instance, we detected a mutation in the acpS gene in both S. tigurinus SCVs. AcpS not only affects the biosynthesis of fatty acids but also of the D-alanylated lipoteichoic acids (LTAs) of bacterial cell walls (41). Modulations in the D-alanyl content of the cell wall directly influence the autolytic mechanism (41).…”

Section: Discussionmentioning

confidence: 99%

“…AcpS not only affects the biosynthesis of fatty acids but also of the D-alanylated lipoteichoic acids (LTAs) of bacterial cell walls (41). Modulations in the D-alanyl content of the cell wall directly influence the autolytic mechanism (41). We hypothesize that AcpS function was affected by the mutation, leading to deficiencies of D-alanylated LTAs, which are inhibitors of cell autolysis (42).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Streptococcus tigurinus Small-Colony Variants Causing Prosthetic Joint Infection by Comparative Whole-Genome Analyses

et al. 2014

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Small-colony variants (SCVs) of bacteria are associated with recurrent and persistent infections. We describe for the first time SCVs of Streptococcus tigurinus in a patient with a prosthetic joint infection. S. tigurinus is a novel pathogen of the Streptococcus mitis group and causes invasive infections. We sought to characterize S. tigurinus SCVs using experimental methods and find possible genetic explanations for their phenotypes. The S. tigurinus SCVs were compared with the wild-type (WT) isolate using phenotypic methods, including growth under different conditions, autolysis, and visualization of the cell ultrastructure by use of transmission electron microscopy (TEM). Furthermore, comparative genome analyses were performed. The S. tigurinus SCVs displayed reduced growth compared to the WT and showed either a very stable or a fluctuating SCV phenotype. TEM analyses revealed major alterations in cell separation and morphological abnormalities, which were partially explained by impaired autolytic behavior. Intriguingly, the SCVs were more resistant to induced autolysis. Whole-genome sequencing revealed mutations in the genes involved in general cell metabolism, cell division, stringent response, and virulence. Clinically, the patient recovered after a 2-stage exchange of the prosthesis. Comparative whole-genome sequencing in clinical strains is a useful tool for identifying novel genetic signatures leading to the most persistent bacterial forms. The detection of viridans streptococcal SCVs is challenging in a clinical laboratory due to the small colony size. Thus, it is of major clinical importance for microbiologists and clinicians to be aware of viridans streptococcal SCVs, such as those of S. tigurinus, which lead to difficult-to-treat infections.

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Inhibition of the D‐alanine:D‐alanyl carrier protein ligase from Bacillus subtilis increases the bacterium's susceptibility to antibiotics that target the cell wall

Cited by 95 publications

References 46 publications

Siderophore-Based Iron Acquisition and Pathogen Control

Siderophore-Based Iron Acquisition and Pathogen Control

Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids

Characterization of Streptococcus tigurinus Small-Colony Variants Causing Prosthetic Joint Infection by Comparative Whole-Genome Analyses

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