Ribosomally Synthesized Thiopeptide Antibiotics Targeting Elongation Factor Tu

Morris, Rowan P.; Leeds, Jennifer A.; Naegeli, Hans‐Ulrich; Oberer, Lukas; Memmert, Klaus; Weber, Eric; LaMarche, Matthew J.; Parker, Christian N.; Burrer, Nathalie; Esterow, Stacey; Hein, Andreas; Schmitt, E.; Krastel, Philipp

doi:10.1021/ja900488a

Cited by 166 publications

(259 citation statements)

References 41 publications

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“…The thiopeptides are a family of highly modified sulfur‐rich macrocyclic peptides (Figure 14, numbering according to thiomuracin A),76 which have been isolated from diverse sources such as soil bacteria and marine samples 77. While there are now over 100 known thiopeptides, the first member, micrococcin P1 ( 14 ), was isolated in 1948 78.…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

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Targeting Antibiotic Resistance

2016

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Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

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Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

“…In 2009, the isolation of thiomuracins, a novel class of antibiotic thiopeptides, was reported (Novartis) 76. These secondary metabolites, which are produced by a strain of Nonomuraea , are structurally related to GE2270 A and share the same mechanism of action, namely binding to EF‐Tu.…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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“…Most thiazolylpeptides show potent activity against Gram-positive pathogens, yet their poor solubility has limited clinical progress, and only a derivative of GE2270 has entered clinical trials for the topical treatment of acne. 46 Novel members of this class have been described (Figure 2b): thiomuracins 47 belong to the subgroup targeting EF-Tu, with an antibacterial profile similar to GE2270; thiazomycin 48 and philipimycin, 49 which target the 50S subunit, show high activity against Gram-positive strains, and a similar profile to thiostrepton.…”

Section: Improved Variants From Microbial Sourcesmentioning

confidence: 99%

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Donadio¹,

Maffioli²,

Monciardini³

et al. 2010

J Antibiot

223

135

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New antibiotics are necessary to treat microbial pathogens that are becoming increasingly resistant to available treatment. Despite the medical need, the number of newly approved drugs continues to decline. We offer an overview of the pipeline for new antibiotics at different stages, from compounds in clinical development to newly discovered chemical classes. Consistent with historical data, the majority of antibiotics under clinical development are natural products or derivatives thereof. However, many of them also represent improved variants of marketed compounds, with the consequent risk of being only partially effective against the prevailing resistance mechanisms. In the discovery arena, instead, compounds with promising activities have been obtained from microbial sources and from chemical modification of antibiotic classes other than those in clinical use. Furthermore, new natural product scaffolds have also been discovered by ingenious screening programs. After providing selected examples, we offer our view on the future of antibiotic discovery.

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“…In this regard, the chemistry described by these systems is very different. In clostriodiolysin S, an amide carbonyl undergoes activation, as is the case for microcin B17, patellamide, goadsporin, and the recently described thiopeptide family (13)(14)(15)(16)27). Because ClosA contains a C-terminal asparagine, in addition to several Ser, Thr, B, shown is the genetic complementation of Clos genes in GAS M1 Sag mutants.…”

Section: Closa-d Genetic Complementation Studies In Groupmentioning

confidence: 99%

“…ClosBCD resembles the McbBCD-modifying proteins found in the Escherichia coli microcin B17 system and the Prochloron didemni patDG genes of the patellamide biosynthetic gene cluster. This family of natural product toxins was recently shown by several groups to include the thiopeptides, which are nearly ubiquitous in soil-dwelling Bacillus and Streptomyces bacteria (12)(13)(14)(15)(16). In the microcin B17 system, McbB, -C, and -D were shown to be necessary and sufficient for the installation of heterocyclic moieties on C-terminal serine and cysteine residues of the McbA substrate.…”

mentioning

confidence: 99%

Clostridiolysin S, a Post-translationally Modified Biotoxin from Clostridium botulinum

Gonzalez

Lee

Hensler

et al. 2010

Journal of Biological Chemistry

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Through elaboration of its botulinum toxins, Clostridium botulinum produces clinical syndromes of infant botulism, wound botulism, and other invasive infections. Using comparative genomic analysis, an orphan nine-gene cluster was identified in C. botulinum and the related foodborne pathogen Clostridium sporogenes that resembled the biosynthetic machinery for streptolysin S, a key virulence factor from group A Streptococcus responsible for its hallmark ␤-hemolytic phenotype. Genetic complementation, in vitro reconstitution, mass spectral analysis, and plasmid intergrational mutagenesis demonstrate that the streptolysin S-like gene cluster from Clostridium sp. is responsible for the biogenesis of a novel post-translationally modified hemolytic toxin, clostridiolysin S.Microbial virulence and survival are often defined by metabolic output. Among the many molecular species used to give a competitive advantage are hydrogen peroxide, genetically encoded small molecules, siderophores, proteins, and bacteriocins (1, 2). Streptolysin S (SLS) 2 is a well known hemolytic/ cytolytic, ribosomally encoded bacteriocin and virulence factor group A Streptococcus (GAS) (3)(4)(5). To this day, the characteristic ␤-hemolytic phenotype observed on blood agar plates is used as a clinical diagnostic tool for GAS identification. GAS is best known as the agent of acute pharyngitis (strep throat) but also may cause invasive infections, including necrotizing fasciitis and toxic shock syndrome. In the 100-year history of our knowledge of streptococcal bacteria, the precise chemical structure of this toxin has remained elusive, although the discovery of its biosynthetic gene cluster more than a decade ago (4) has guided investigations into its post-translational modification and likely heterocyclic nature (6, 7).Through recent comparative genomic analysis, an SLS-type gene cluster was identified in clostridia species including Clostridium botulinum and Clostridium sporogenes, two diseasecausing bacteria known to endanger food supplies (8 -10). Similar gene clusters were found in Staphylococcus aureus RF122, Bacillus thuringiensis, Streptococcus iniae, and Listeria monocytogenes 4b. The L. monocytogenes 4b strain is the primary serotype and causative agent for outbreaks of listeriosis (11). The S. aureus RF122 strain is responsible for bovine mastitis. S. iniae is a cytotoxic fish pathogen. This suggests that a shared metabolic output of these pathogens including SLS-like toxins may contribute to their pathogenic potential (11).Each of these SLS family gene clusters contains a similar set of genes. For instance, in C. botulinum and C. sporogenes, the closA-I genes are related by sequence to sagA-I from GAS (see Fig. 1A). Of these genes, ClosF is a protein of unknown function. ClosG, -H, and -I are ABC transporters and therefore are likely to be responsible for exporting the mature hemolytic product. ClosA is the prepropeptide (structural peptide) that is post-translationally modified to form the propeptide. ClosE has been annotated as an i...

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Ribosomally Synthesized Thiopeptide Antibiotics Targeting Elongation Factor Tu

Cited by 166 publications

References 41 publications

Targeting Antibiotic Resistance

Targeting Antibiotic Resistance

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Clostridiolysin S, a Post-translationally Modified Biotoxin from Clostridium botulinum

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