The Expanding Role of Lipid II as a Target for Lantibiotics

Martin, Nathaniel I.; Breukink, Eefjan

doi:10.2217/17460913.2.5.513

Cited by 64 publications

(46 citation statements)

References 105 publications

(101 reference statements)

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“…The mevalonate pathway is required to make undecaprenyl pyrophosphate and lipid II (43). The consequence of this upregulation in the fabT deletion mutant strain might be increased production of lipid II, potentially leading to (i) in- creased resistance to cationic antimicrobial peptides (CAMPs) and lantibiotics that target lipid II (44)(45)(46) and (ii) higher levels of peptidoglycan (PG) and other envelope components that also are targets for CAMPs (47,48). The gene Spy_0124 (sloR), encoding a regulator involved in metal homeostasis, was also significantly upregulated by 10.3-fold in the fabT deletion mutant during mid-exponential phase at 35°C.…”

Section: Identification Of Acquired Polymorphisms In Serotype M1 Stramentioning

confidence: 99%

Genomic Landscape of Intrahost Variation in Group A Streptococcus: Repeated and Abundant Mutational Inactivation of the fabT Gene Encoding a Regulator of Fatty Acid Synthesis

et al. 2016

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dTo obtain new information about Streptococcus pyogenes intrahost genetic variation during invasive infection, we sequenced the genomes of 2,954 serotype M1 strains recovered from a nonhuman primate experimental model of necrotizing fasciitis. A total of 644 strains (21.8%) acquired polymorphisms relative to the input parental strain. The fabT gene, encoding a transcriptional regulator of fatty acid biosynthesis genes, contained 54.5% of these changes. The great majority of polymorphisms were predicted to deleteriously alter FabT function. Transcriptome-sequencing (RNA-seq) analysis of a wild-type strain and an isogenic fabT deletion mutant strain found that between 3.7 and 28.5% of the S. pyogenes transcripts were differentially expressed, depending on the growth temperature (35°C or 40°C) and growth phase (mid-exponential or stationary phase). Genes implicated in fatty acid synthesis and lipid metabolism were significantly upregulated in the fabT deletion mutant strain. FabT also directly or indirectly regulated central carbon metabolism genes, including pyruvate hub enzymes and fermentation pathways and virulence genes. Deletion of fabT decreased virulence in a nonhuman primate model of necrotizing fasciitis. In addition, the fabT deletion strain had significantly decreased survival in human whole blood and during phagocytic interaction with polymorphonuclear leukocytes ex vivo. We conclude that FabT mutant progeny arise during infection, constitute a metabolically distinct subpopulation, and are less virulent in the experimental models used here. Streptococcus pyogenes is a Gram-positive bacterium that causes a range of diseases in humans, including pharyngitis, superficial and deep skin infections, acute rheumatic fever, poststreptococcal glomerulonephritis, bacteremia, and necrotizing fasciitis ("flesh-eating disease") (1, 2). Globally, there are over 700 million group A streptococcus (GAS) infections annually (3). It has been estimated that 9,000 to 11,500 cases of invasive GAS disease occur each year in the United States, resulting in 1,000 to 1,800 deaths annually (4; http://www.cdc.gov). Rheumatic fever, necrotizing fasciitis, and toxic shock syndrome are responsible for the high morbidity and mortality rates due to GAS infections (5).Advances in DNA sequencing and related technologies have facilitated genome-wide dissection of genetic events involved in colonization (6), immune evasion (7), virulence (8-10), and the evolution and spread of highly virulent S. pyogenes clones (11-13). To advance our understanding of S. pyogenes molecular-pathogenesis events occurring during invasive infection, we performed whole-genome sequencing of 2,954 isolates recovered from a nonhuman primate model of necrotizing fasciitis. The resulting genome sequence data stimulated us to construct an isogenic fabT deletion mutant strain and to compare its global transcriptome and virulence attributes with those of the wild-type parental strain. MATERIALS AND METHODSBacterial strains and growth conditions. Escherichia coli strai...

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Section: Identification Of Acquired Polymorphisms In Serotype M1 Stramentioning

confidence: 99%

Genomic Landscape of Intrahost Variation in Group A Streptococcus: Repeated and Abundant Mutational Inactivation of the fabT Gene Encoding a Regulator of Fatty Acid Synthesis

et al. 2016

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“…This system is transcriptionally activated by exposure to alkaline shock, organic solvents, detergents, secretion stress, and notably lipid II cycle inhibitors such as the antibiotics vancomycin and bacitracin, the bacteriocin nisin, and cationic antimicrobial peptides (39,51); hence, its cogname, lipid IIinteracting antibiotics LiaRS. Lipid II contains the complete peptidoglycan (PG) subunit linked to the membrane-embedded lipid carrier C 55 -isoprenyl phosphate (36,60). The molecule "flips" between the cytoplasmic and extracellular faces of the cell membrane in a dynamic process (referred to as the lipid II cycle) essential for translocating PG precursors for cell wall biosynthesis (36,60).…”

mentioning

confidence: 99%

“…Lipid II contains the complete peptidoglycan (PG) subunit linked to the membrane-embedded lipid carrier C 55 -isoprenyl phosphate (36,60). The molecule "flips" between the cytoplasmic and extracellular faces of the cell membrane in a dynamic process (referred to as the lipid II cycle) essential for translocating PG precursors for cell wall biosynthesis (36,60). The Lipid II cycle is considered the rate-limiting step of PG polymer biosynthesis and, consequently, the subject of intense scrutiny in the development of novel inhibitors that target or exploit this process (9).…”

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confidence: 99%

The LiaFSR System Regulates the Cell Envelope Stress Response inStreptococcus mutans

et al. 2009

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Maintaining cell envelope integrity is critical for bacterial survival, including bacteria living in a complex and dynamic environment such as the human oral cavity. Streptococcus mutans, a major etiological agent of dental caries, uses two-component signal transduction systems (TCSTSs) to monitor and respond to various environmental stimuli. Previous studies have shown that the LiaSR TCSTS in S. mutans regulates virulence traits such as acid tolerance and biofilm formation. Although not examined in streptococci, homologs of LiaSR are widely disseminated in Firmicutes and function as part of the cell envelope stress response network. We describe here liaSR and its upstream liaF gene in the cell envelope stress tolerance of S. mutans strain UA159. Transcriptional analysis established liaSR as part of the pentacistronic liaFSR-ppiB-pnpB operon. A survey of cell envelope antimicrobials revealed that mutants deficient in one or all of the liaFSR genes were susceptible to Lipid II cycle interfering antibiotics and to chemicals that perturbed the cell membrane integrity. These compounds induced liaR transcription in a concentration-dependent manner. Notably, under bacitracin stress conditions, the LiaFSR signaling system was shown to induce transcription of several genes involved in membrane protein synthesis, peptidoglycan biosynthesis, envelope chaperone/proteases, and transcriptional regulators. In the absence of an inducer such as bacitracin, LiaF repressed LiaR-regulated expression, whereas supplementing cultures with bacitracin resulted in derepression of liaSR. While LiaF appears to be an integral component of the LiaSR signaling cascade, taken collectively, we report a novel role for LiaFSR in sensing cell envelope stress and preserving envelope integrity in S. mutans.

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“…Nisin, obtained by fermentation of Lactobacillus lactis on natural substrates such as milk or dextrose, is widely used as a safe food preservation additive (Cleveland et al 2001), since orally administered nisin is completely degraded by digesting enzymes in the stomach. Nisin binds to the pyrophosphate moiety of lipid II (Scheme 5) forming a phosphate cage that prevents the release of the peptidoglycan subunits and leads to the formation of a pore in the membrane via intermembrane assembly of a nisin-lipid II 8:4-complex (Hsu et al 2004;Bauer and Dicks 2005;Martin and Breukink 2007). …”

Section: Lessons Learned From Druggable Targets In Bacteriamentioning

confidence: 99%

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

Klahn

Brönstrup

2016

Current Topics in Microbiology and Immunology

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Abstract:The development of bacterial resistance against current antibiotic drugs necessitates a continuous renewal of the arsenal of efficacious drugs. This imperative has not been met by the output of antibiotic research and development of the past decades for various reasons, including the declining efforts of large pharma companies in this area. Moreover, the majority of novel antibiotics are chemical derivatives of existing structures that represent mostly step innovations, implying that the available chemical space may be exhausted. This review negates this impression by showcasing recent achievements in lead finding and optimization of antibiotics that have novel or unexplored chemical structures. Not surprisingly, many of the novel structural templates like teixobactins, lysocin, griselimycin, or the albicidin/cystobactamid pair were discovered from natural sources. Additional compounds were obtained from the screening of synthetic libraries and chemical synthesis, including the gyrase-inhibiting NTBI s a d spiropyrimidinetrione, the tarocin and targocil inhibitors of wall teichoic acid synthesis, or the boronates and diazabicyclo[3.2

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The Expanding Role of Lipid II as a Target for Lantibiotics

Cited by 64 publications

References 105 publications

Genomic Landscape of Intrahost Variation in Group A Streptococcus: Repeated and Abundant Mutational Inactivation of the fabT Gene Encoding a Regulator of Fatty Acid Synthesis

Genomic Landscape of Intrahost Variation in Group A Streptococcus: Repeated and Abundant Mutational Inactivation of the fabT Gene Encoding a Regulator of Fatty Acid Synthesis

The LiaFSR System Regulates the Cell Envelope Stress Response inStreptococcus mutans

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

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