Multipronged approach for engineering novel peptide analogues of existing lantibiotics

Escano, Jerome; Smith, Linda L.

doi:10.1517/17460441.2015.1049527

Cited by 18 publications

(18 citation statements)

References 114 publications

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“…Nisin activity against B. subtilis and M. luteus was reduced by 4-fold and 2-fold, respectively (MICs, 2.0 g/ml and 1.0 g/ml). To further clarify a mechanism of action for the loss of activity in the MIC competition assay, confocal microscopy was used to observe nisin binding as previously described (31). If mu1140-COOH was still binding to lipid II in vivo, it should have competitively inhibited the binding of fluorescein-labeled nisin (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Increasing activity or developing new uses for existing lantibiotics has been a goal of many researchers in the field and has been achieved through a variety of methods, such as amino acid substitutions and the use of nonproteogenic amino acids (31,42). Semisynthetic analogues of lantibiotics have been produced by chemically modifying lantibiotics (43,44).…”

Section: Discussionmentioning

confidence: 99%

“…NVB302, an analogue of actagardine which has successfully undergone phase 1 clinical trials, has a diaminoheptane tail attached to the C terminus of the lantibiotic (32). Additionally, lantibiotics can be produced through solid-phase peptide synthesis (SPPS) using orthogonally protected lanthionine rings (31,33). The AviCys residue complicates the further development of the epidermin group of lantibiotics using these methods.…”

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confidence: 99%

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Carboxyl Analogue of Mutacin 1140, a Scaffold for Lead Antibacterial Discovery

Escano

Ravichandran

Salamat

et al. 2017

Appl Environ Microbiol

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Mutacin 1140 belongs to the epidermin group of lantibiotics. Epidermin class lantibiotics are ribosomally synthesized and posttranslationally modified antibiotics with potent activity against Gram-positive bacteria. In particular, this class is effective at targeting drug-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium tuberculosis, and Clostridium difficile.residue is derived from a decarboxylation of a terminal cysteine that is involved in lanthionine ring formation. Studies on mutacin 1140 have revealed new insight into the structural importance of the C-terminal AviCys residue. A C-terminal carboxyl analogue of mutacin 1140 was engineered. Capping the C-terminal carboxyl group with a primary amine restores bioactivity and affords a novel opportunity to synthesize new analogues. A C-terminal fluorescein-labeled mutacin 1140 analogue traps lipid II into a large lipid II lantibiotic complex, similar to that observed in vivo for the lantibiotic nisin. A C-terminal carboxyl analogue of mutacin 1140 competitively inhibits the activity of native mutacin 1140 and nisin. The presence of a C-terminal carboxyl group prevents the formation of the large lipid II lantibiotic complexes but does not prevent the binding of the lantibiotic to lipid II. IMPORTANCE This study addressed the importance of the C-terminal S-[(Z)-2-aminovinyl]-D-cysteine (AviCys) residue for antibacterial activity. We have learned that the posttranslational modification for making the AviCys residue is presumably important for the lateral assembly mechanism of activity that traps lipid II into a large complex. The C-terminal carboxyl analogue of this class of lantibiotics is agreeable to the addition of a wide variety of substrates. The addition of fluorescein enabled in vivo visualization of the epidermin class of lantibiotics in action. These results are significant because, as we demonstrate, the presence of the AviCys residue is not essential for bioactivity, but, more importantly, the removal of the carboxyl group is essential. The ability to make a C-terminal carboxyl analogue that is modifiable will facilitate the synthesis of novel analogues of the epidermin class of lantibiotics that can be developed for new applications.KEYWORDS lantibiotic, decarboxylation, mutacin 1140, nisin L antibiotics, or lanthionine-containing antibiotics, are characterized by their posttranslational modifications (PTMs) (1). Dehydrations of serine and threonine residues into dehydroalanine and dehydrobutyrine residues, respectively, are a common modification found in lantibiotics. These dehydrated residues can be cyclized with cysteines to form thioether bridges, which are called lanthionines (2, 3). The unmodified lantibiotic is encoded by the gene lanA. The genes for biosynthesis and regulation are generally grouped together in a biosynthetic gene cluster. In class I lantibiotics, dehydrations are carried out by the dehydratase, LanB. Lanthionine ring formation is catalyzed by LanC. Lantibiotics can ...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Carboxyl Analogue of Mutacin 1140, a Scaffold for Lead Antibacterial Discovery

Escano

Ravichandran

Salamat

et al. 2017

Appl Environ Microbiol

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“…We will not consider general modifications of well-known peptidyl antibi-otics, which have been reviewed elsewhere. [24] Herein,w ew ill only considers tructuralm odifications of the furanoser ing and the nucleobase of the nucleoside unit of NDPs,w ith as pecial focus on targeting GTs.…”

Section: Introductionmentioning

confidence: 99%

Nucleoside Diphosphate Sugar Analogues that Target Glycosyltransferases

et al. 2016

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Glycosyltransferases (GTs) are enzymes that transfer carbohydrates to ar ange of substrates and they play af undamental role in the recognition processes associated with severald iseases.T he design of glycomimeticso fn ucleoside diphosphate( NDP) sugars-the natural substrates that act as inhibitors or modulators of GTs-is not only necessary for the development of glycan-based therapeutic drugs, but is also ac rucial toolf or understanding their mechanismso fa ction.W hilst al arge number of inhibitors that consist of modifications of the carbohydrate unit and the pyrophosphate linkageh ave been designed,l ess attention has been paidt om odifications at the ribose moiety and the nucleobase. However,i nr ecent years, promising results have been obtainedt hrough such variations, which were prompted by the initial interest in the photolabeling of enzymes to study their structure. In this Focus Review,w e survey recentp rogress in the synthesis of NDP-sugar analogues that are modified at the ribose moiety or at the heterocyclic base.The ORCID identification number(s) for the author(s) of this articlecan be found under http://dx.

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“…[76] Nowadays, the total synthesis of lantibiotics is performed via biosynthetic approaches or chemically using SPPS. [77] This last high yieldinga pproachi se speciallyu seful for the lengthy multistep protocolo fp eptidee longation. The preparation of the bis(desmethyl) analog of lantibiotic lacticin 3147 A2 using SPPS was describedb yP attabiraman et al in 2008.…”

Section: Applicationmentioning

confidence: 99%

Progress in Lanthionine and Protected Lanthionine Synthesis

Denoël

Lemaire

Luxen

2018

Chemistry A European J

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Lanthionine (Lan), a non‐proteinogenic natural amino acid, is an essential component of peptidoglycan found in the cell wall of Fusobacterium species. Lan and β‐methyllanthionine are also key constituents in lantibiotics, a prevalent class of peptide antibiotics. The development of those new antibacterial drugs with enhanced properties is the focus of recent research. Since multiple isomers of Lan are possible, a regio‐ and diastereoselective synthesis is challenging. This comprehensive review summarizes the known chemical syntheses of lanthionine from various precursors (e.g., β‐chloroalanine, cystine, dehydroalanine, β‐iodoalanine, aziridine, serine lactone, sulfamidate) since 1941. Methods for preparation of unprotected, protected, orthogonally protected, and mutually orthogonally protected lanthionine with relevant experimental details and perspectives on their usefulness are provided. The potential of these Lan derivatives is illustrated by one recent application.

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Multipronged approach for engineering novel peptide analogues of existing lantibiotics

Cited by 18 publications

References 114 publications

Carboxyl Analogue of Mutacin 1140, a Scaffold for Lead Antibacterial Discovery

Carboxyl Analogue of Mutacin 1140, a Scaffold for Lead Antibacterial Discovery

Nucleoside Diphosphate Sugar Analogues that Target Glycosyltransferases

Progress in Lanthionine and Protected Lanthionine Synthesis

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