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1.
Cell ; 175(4): 1045-1058.e16, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30388443

RESUMEN

Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (thus causing disease) and allow design of non-toxic "lipid-altered" tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed the design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo, providing a promising new class of antimicrobial drug.


Asunto(s)
Antibióticos Antituberculosos/farmacología , Trastornos Congénitos de Glicosilación/metabolismo , Inhibidores Enzimáticos/farmacología , N-Acetilglucosaminiltransferasas/química , Animales , Antibióticos Antituberculosos/química , Sitios de Unión , Trastornos Congénitos de Glicosilación/genética , Inhibidores Enzimáticos/química , Femenino , Células HEK293 , Células Hep G2 , Humanos , Metabolismo de los Lípidos , Ratones , Simulación del Acoplamiento Molecular , Mutación , N-Acetilglucosaminiltransferasas/antagonistas & inhibidores , N-Acetilglucosaminiltransferasas/genética , N-Acetilglucosaminiltransferasas/metabolismo , Unión Proteica , Células Sf9 , Spodoptera , Tunicamicina/química , Tunicamicina/farmacología , Uridina Difosfato Ácido Glucurónico/química , Uridina Difosfato Ácido Glucurónico/metabolismo
2.
Proc Natl Acad Sci U S A ; 121(29): e2315310121, 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-38990944

RESUMEN

Bacitracin is a macrocyclic peptide antibiotic that is widely used as a topical treatment for infections caused by gram-positive bacteria. Mechanistically, bacitracin targets bacteria by specifically binding to the phospholipid undecaprenyl pyrophosphate (C55PP), which plays a key role in the bacterial lipid II cycle. Recent crystallographic studies have shown that when bound to C55PP, bacitracin adopts a highly ordered amphipathic conformation. In doing so, all hydrophobic side chains align on one face of the bacitracin-C55PP complex, presumably interacting with the bacterial cell membrane. These insights led us to undertake structure-activity investigations into the individual contribution of the nonpolar amino acids found in bacitracin. To achieve this we designed, synthesized, and evaluated a series of bacitracin analogues, a number of which were found to exhibit significantly enhanced antibacterial activity against clinically relevant, drug-resistant pathogens. As for the natural product, these next-generation bacitracins were found to form stable complexes with C55PP. The structure-activity insights thus obtained serve to inform the design of C55PP-targeting antibiotics, a key and underexploited antibacterial strategy.


Asunto(s)
Antibacterianos , Bacitracina , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/química , Bacitracina/farmacología , Bacitracina/química , Relación Estructura-Actividad , Farmacorresistencia Bacteriana/efectos de los fármacos , Vancomicina/farmacología , Vancomicina/química , Vancomicina/análogos & derivados , Diseño de Fármacos , Fosfatos de Poliisoprenilo/metabolismo , Fosfatos de Poliisoprenilo/química , Fosfatos de Poliisoprenilo/farmacología
3.
Beilstein J Org Chem ; 20: 220-227, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38352069

RESUMEN

Lipid II is an essential glycolipid found in bacteria. Accessing this valuable cell wall precursor is important both for studying cell wall synthesis and for studying/identifying novel antimicrobial compounds. Herein, we describe optimizations to the modular chemical synthesis of lipid II and unnatural analogues. In particular, the glycosylation step, a critical step in the formation of the central disaccharide unit (GlcNAc-MurNAc), was optimized. This was achieved by employing the use of glycosyl donors with diverse leaving groups. The key advantage of this approach lies in its adaptability, allowing for the generation of a wide array of analogues through the incorporation of alternative building blocks at different stages of synthesis.

4.
Chembiochem ; 21(6): 789-792, 2020 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-31552694

RESUMEN

The prevalence of life-threatening, drug-resistant microbial infections has challenged researchers to consider alternatives to currently available antibiotics. Teixobactin is a recently discovered "resistance-proof" antimicrobial peptide that targets the bacterial cell wall precursor lipid II. In doing so, teixobactin exhibits potent antimicrobial activity against a wide range of Gram-positive organisms. Herein we demonstrate that teixobactin and several structural analogues are capable of binding lipid II from both Gram-positive and Gram-negative bacteria. Furthermore, we show that when combined with known outer membrane-disrupting peptides, teixobactin is active against Gram-negative organisms.


Asunto(s)
Antibacterianos/farmacología , Pared Celular/efectos de los fármacos , Depsipéptidos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Uridina Difosfato Ácido N-Acetilmurámico/análogos & derivados , Antibacterianos/química , Sitios de Unión/efectos de los fármacos , Depsipéptidos/química , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Uridina Difosfato Ácido N-Acetilmurámico/antagonistas & inhibidores
5.
Proc Natl Acad Sci U S A ; 113(41): 11561-11566, 2016 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-27688760

RESUMEN

Tridecaptin A1 (TriA1) is a nonribosomal lipopeptide with selective antimicrobial activity against Gram-negative bacteria. Here we show that TriA1 exerts its bactericidal effect by binding to the bacterial cell-wall precursor lipid II on the inner membrane, disrupting the proton motive force. Biochemical and biophysical assays show that binding to the Gram-negative variant of lipid II is required for membrane disruption and that only the proton gradient is dispersed. The NMR solution structure of TriA1 in dodecylphosphocholine micelles with lipid II has been determined, and molecular modeling was used to provide a structural model of the TriA1-lipid II complex. These results suggest that TriA1 kills Gram-negative bacteria by a mechanism of action using a lipid-II-binding motif.


Asunto(s)
Antibacterianos/farmacología , Lípidos/química , Lipopéptidos/farmacología , Péptidos/farmacología , Antibacterianos/química , Antibacterianos/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Farmacorresistencia Bacteriana/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Cinética , Lipopéptidos/química , Lipopéptidos/metabolismo , Espectroscopía de Resonancia Magnética , Micelas , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Péptidos/química , Péptidos/metabolismo , Fuerza Protón-Motriz
6.
J Am Chem Soc ; 139(49): 17803-17810, 2017 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-29164875

RESUMEN

Lacticin 3147 is a two peptide lantibiotc (LtnA1 and LtnA2) that displays nanomolar activity against many Gram-positive bacteria. Lacticin 3147 may exert its antimicrobial effect by several mechanisms. Isothermal titration calorimetry experiments show that only LtnA1 binds to the peptidoglycan precursor lipid II, which could inhibit peptidoglycan biosynthesis. An experimentally supported model of the resulting complex suggests that the key binding partners are the C-terminus of LtnA1 and pyrophosphate of lipid II. A combination of in vivo and in vitro assays indicates that LtnA1 and LtnA2 can induce rapid membrane lysis without the need for lipid II binding. However, the presence of lipid II substantially increases the activity of lacticin 3147. Furthermore, studies with synthetic LtnA2 analogues containing either desmethyl- or oxa-lanthionine rings confirm that the precise geometry of these rings is essential for this synergistic activity.

7.
Med Res Rev ; 36(1): 4-31, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24866700

RESUMEN

The emergence of multidrug-resistant bacteria has placed a strain on health care systems and highlighted the need for new classes of antibiotics. Bacterial lipopeptides are secondary metabolites, generally produced by nonribosomal peptide synthetases that often exhibit broad-spectrum antimicrobial activity. Only two new structural types of antibiotics have entered the market in the last 40 years, linezolid and the bacterial lipopeptide daptomycin. A wide variety of bacteria produce lipopeptides, however Bacillus and Paenibacillus spp. in particular have yielded several potent antimicrobial lipopeptides. Many of the lipopeptides produced by these bacteria have been known for decades and represent a potential gold mine of antibiotic candidates. This list includes the polymyxins, octapeptins, polypeptins, iturins, surfactins, fengycins, fusaricidins, and tridecaptins, as well as some novel examples, including the kurstakins. These lipopeptides have a wide variety of activities, ranging from antibacterial and antifungal, to anticancer and antiviral. This review presents a reasonably comprehensive list of each class of lipopeptide and their known homologues. Emphasis has been placed on their antimicrobial activities, as well other potential applications for this interesting class of substances.


Asunto(s)
Antibacterianos/química , Bacillus/química , Infecciones Bacterianas/tratamiento farmacológico , Química Farmacéutica/métodos , Lipopéptidos/química , Paenibacillus/química , Animales , Evaluación Preclínica de Medicamentos , Farmacorresistencia Bacteriana Múltiple , Humanos , Polimixinas/química , Ratas
8.
Org Biomol Chem ; 13(21): 6073-81, 2015 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-25959079

RESUMEN

Previously other groups had reported that Paenibacillus polymyxa NRRL B-30507 produces SRCAM 37, a type IIA bacteriocin with antimicrobial activity against Campylobacter jejuni. Genome sequencing and isolation of antimicrobial compounds from this P. polymyxa strain show that the antimicrobial activity is due to polymyxins and tridecaptin B1. The complete structural assignment, synthesis, and antimicrobial profile of tridecaptin B1 is reported, as well as the putative gene cluster responsible for its biosynthesis. This peptide displays strong activity against multidrug resistant Gram-negative bacteria, a finding that is timely to the current problem of antibiotic resistance.


Asunto(s)
Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Paenibacillus/química , Péptidos/aislamiento & purificación , Péptidos/farmacología , Secuencia de Aminoácidos , Antibacterianos/química , Antibacterianos/metabolismo , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Humanos , Datos de Secuencia Molecular , Familia de Multigenes , Paenibacillus/genética , Paenibacillus/metabolismo , Péptidos/química , Péptidos/genética , Polimixinas/química , Polimixinas/aislamiento & purificación , Polimixinas/metabolismo , Polimixinas/farmacología
9.
Chembiochem ; 15(9): 1295-9, 2014 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-24816483

RESUMEN

Tridecaptin A1 is a linear antimicrobial lipopeptide comprised of 13 amino acids, including three diaminobutyric acid (Dab) residues. It displays potent activity against Gram-negative bacteria, including multidrug-resistant strains. Using solid-phase peptide synthesis, we performed an alanine scan of a fully active analogue, octyl-tridecaptin A1 , to determine key residues responsible for activity. The synthetic analogues were tested against ten organisms, both Gram-positive and Gram-negative bacteria. Modification of D-Dab8 abolished activity, and marked decreases were observed with substitution of D-allo-Ile12 and D-Trp5. Circular dichroism showed that octyl-tridecaptin A1 adopts a secondary structure in the presence of model phospholipid membranes, which was weakened by D-Dab8-D-Ala, D-allo-Ile12-D-Ala, and D-Trp5-D-Ala substitutions. The antimicrobial activity of the analogues is directly correlated to their ability to adopt a stable secondary structure in a membrane environment.


Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Lipopéptidos/farmacología , Fosfolípidos/química , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Lipopéptidos/síntesis química , Lipopéptidos/química , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Relación Estructura-Actividad
10.
Chembiochem ; 15(2): 243-9, 2014 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-24382692

RESUMEN

Bacillus circulans NRRL B-30644 (now Paenibacillus terrae) was previously reported to produce SRCAM 1580, a bacteriocin active against the food pathogen Campylobacter jejuni. We have been unable to isolate SRCAM 1580, and did not find any genetic determinants in the genome of this strain. We now report the reassignment of this activity to the lipopeptide tridecaptin A1. Structural characterization of tridecaptin A1 was achieved through NMR, MS/MS and GC-MS studies. The structure was confirmed through the first chemical synthesis of tridecaptin A1, which also revealed the stereochemistry of the lipid chain. The impact of this stereochemistry on antimicrobial activity was examined. The biosynthetic machinery responsible for tridecaptin production was identified through bioinformatic analyses. P. terrae NRRL B-30644 also produces paenicidin B, a novel lantibiotic active against Gram-positive bacteria. MS/MS analyses indicate that this lantibiotic is structurally similar to paenicidin A.


Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Campylobacter jejuni/efectos de los fármacos , Lipopéptidos/química , Lipopéptidos/farmacología , Péptidos/química , Péptidos/farmacología , Secuencia de Aminoácidos , Antibacterianos/metabolismo , Bacteriocinas/biosíntesis , Bacteriocinas/química , Lípidos/química , Lipopéptidos/biosíntesis , Datos de Secuencia Molecular , Familia de Multigenes , Paenibacillus/genética , Paenibacillus/metabolismo , Péptidos/genética , Estereoisomerismo
11.
ACS Chem Biol ; 19(5): 1106-1115, 2024 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-38602492

RESUMEN

The prevalence of multidrug-resistant (MDR) pathogens combined with a decline in antibiotic discovery presents a major challenge for health care. To refill the discovery pipeline, we need to find new ways to uncover new chemical entities. Here, we report the global genome mining-guided discovery of new lipopeptide antibiotics tridecaptin A5 and tridecaptin D, which exhibit unusual bioactivities within their class. The change in the antibacterial spectrum of Oct-TriA5 was explained solely by a Phe to Trp substitution as compared to Oct-TriA1, while Oct-TriD contained 6 substitutions. Metabolomic analysis of producer Paenibacillus sp. JJ-21 validated the predicted amino acid sequence of tridecaptin A5. Screening of tridecaptin analogues substituted at position 9 identified Oct-His9 as a potent congener with exceptional efficacy against Pseudomonas aeruginosa and reduced hemolytic and cytotoxic properties. Our work highlights the promise of tridecaptin analogues to combat MDR pathogens.


Asunto(s)
Antibacterianos , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa , Antibacterianos/farmacología , Antibacterianos/química , Pseudomonas aeruginosa/efectos de los fármacos , Humanos , Especificidad del Huésped , Descubrimiento de Drogas , Lipopéptidos/farmacología , Lipopéptidos/química , Péptidos
12.
ACS Chem Biol ; 19(5): 1125-1130, 2024 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-38712757

RESUMEN

There remains a critical need for new antibiotics against multi-drug-resistant Gram-negative bacteria, a major global threat that continues to impact mortality rates. Lipoprotein signal peptidase II is an essential enzyme in the lipoprotein biosynthetic pathway of Gram-negative bacteria, making it an attractive target for antibacterial drug discovery. Although natural inhibitors of LspA have been identified, such as the cyclic depsipeptide globomycin, poor stability and production difficulties limit their use in a clinical setting. We harness computational design to generate stable de novo cyclic peptide analogues of globomycin. Only 12 peptides needed to be synthesized and tested to yield potent inhibitors, avoiding costly preparation of large libraries and screening campaigns. The most potent analogues showed comparable or better antimicrobial activity than globomycin in microdilution assays against ESKAPE-E pathogens. This work highlights computational design as a general strategy to combat antibiotic resistance.


Asunto(s)
Antibacterianos , Diseño de Fármacos , Péptidos Cíclicos , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/química , Péptidos Cíclicos/síntesis química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Pruebas de Sensibilidad Microbiana , Depsipéptidos/farmacología , Depsipéptidos/química , Lipoproteínas/química , Lipoproteínas/metabolismo , Lipoproteínas/farmacología , Lipoproteínas/antagonistas & inhibidores , Proteínas Bacterianas , Péptidos , Ácido Aspártico Endopeptidasas
13.
Nat Microbiol ; 9(7): 1778-1791, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38783023

RESUMEN

Antimicrobial resistance is a leading cause of mortality, calling for the development of new antibiotics. The fungal antibiotic plectasin is a eukaryotic host defence peptide that blocks bacterial cell wall synthesis. Here, using a combination of solid-state nuclear magnetic resonance, atomic force microscopy and activity assays, we show that plectasin uses a calcium-sensitive supramolecular killing mechanism. Efficient and selective binding of the target lipid II, a cell wall precursor with an irreplaceable pyrophosphate, is achieved by the oligomerization of plectasin into dense supra-structures that only form on bacterial membranes that comprise lipid II. Oligomerization and target binding of plectasin are interdependent and are enhanced by the coordination of calcium ions to plectasin's prominent anionic patch, causing allosteric changes that markedly improve the activity of the antibiotic. Structural knowledge of how host defence peptides impair cell wall synthesis will likely enable the development of superior drug candidates.


Asunto(s)
Calcio , Pared Celular , Péptidos , Uridina Difosfato Ácido N-Acetilmurámico , Pared Celular/metabolismo , Pared Celular/efectos de los fármacos , Pared Celular/química , Calcio/metabolismo , Péptidos/farmacología , Péptidos/metabolismo , Péptidos/química , Uridina Difosfato Ácido N-Acetilmurámico/análogos & derivados , Uridina Difosfato Ácido N-Acetilmurámico/metabolismo , Uridina Difosfato Ácido N-Acetilmurámico/química , Microscopía de Fuerza Atómica , Antibacterianos/farmacología , Antibacterianos/química , Espectroscopía de Resonancia Magnética , Unión Proteica
14.
Org Biomol Chem ; 11(4): 630-9, 2013 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-23212663

RESUMEN

A systematic study of the ring-closing metathesis (RCM) of unprotected oxytocin and crotalphine peptide analogues in water is reported. The replacement of cysteine with S-allyl cysteine enables RCM to proceed readily in water containing excess MgCl(2) with 30% t-BuOH as a co-solvent. The presence of the sulfur atom is vital for efficient aqueous RCM to occur, with non-sulfur containing analogues undergoing RCM in low yields.


Asunto(s)
Oxitocina/análogos & derivados , Oxitocina/síntesis química , Péptidos/química , Péptidos/síntesis química , Agua/química , Secuencia de Aminoácidos , Interacciones Hidrofóbicas e Hidrofílicas , Datos de Secuencia Molecular
15.
Chem Commun (Camb) ; 59(50): 7685-7703, 2023 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-37219335

RESUMEN

Since Fleming's discovery of penicillin nearly a century ago, a bounty of natural product antibiotics have been discovered, many of which continue to be of clinical importance today. The structural diversity encountered among nature's repertoire of antibiotics is mirrored by the varying mechanisms of action by which they selectively target and kill bacterial cells. The ability for bacteria to construct and maintain a strong cell wall is essential for their robust growth and survival under a range of conditions. However, the need to maintain the cell wall also presents a vulnerability that is exploited by many natural antibiotics. Bacterial cell wall biosynthesis involves both the construction of complex membrane-bound precursor molecules and their subsequent crosslinking by dedicated enzymes. Interestingly, many naturally occurring antibiotics function not by directly inhibiting the enzymes associated with cell wall biosynthesis, but rather by binding tightly to their membrane-bound substrates. Such substrate sequestration mechanisms are comparatively rare outside of the antibiotics space with most small-molecule drug discovery programs instead aimed at developing inhibitors of target enzymes. In this feature article we provide the reader with an overview of the unique and ever increasing family of natural product antibiotics known to specifically function by binding to membrane-anchored bacterial cell wall precursors. In doing so, we highlight both our own contributions to the field as well as those made by other researchers engaged in exploring the potential offered by antibiotics that target bacterial cell wall precursors.


Asunto(s)
Antibacterianos , Productos Biológicos , Antibacterianos/química , Bacterias/metabolismo , Pared Celular/metabolismo , Membrana Celular/metabolismo , Productos Biológicos/metabolismo
16.
J Med Chem ; 66(8): 6002-6009, 2023 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-37071814

RESUMEN

Brevicidine and laterocidine are macrocyclic lipodepsipeptides with selective activity against Gram-negative bacteria, including colistin-resistant strains. Previously, the macrocyclic core of these peptides was thought essential for antibacterial activity. In this study, we show that C-terminal amidation of linear brevicidine and laterocidine scaffolds, and substitution of the native Thr9, yields linear analogues that retain the potent antibacterial activity and low hemolysis of the parent compounds. Furthermore, an alanine scan of both peptides revealed that the aromatic and basic amino acids within the common central scaffold are essential for antibacterial activity. This linearization strategy for modification of cyclic peptides is a highly effective way to reduce the time and cost of peptide synthesis and may be applicable to other non-ribosomal antibacterial peptides.


Asunto(s)
Antibacterianos , Lipopéptidos , Lipopéptidos/química , Antibacterianos/química , Péptidos Cíclicos/química , Bacterias Gramnegativas , Técnicas de Química Sintética , Pruebas de Sensibilidad Microbiana
17.
RSC Med Chem ; 13(12): 1640-1643, 2022 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-36545437

RESUMEN

The brevicidine and laterocidine family of lipopeptide antibiotics exhibit strong activity against multidrug-resistant Gram-negative bacteria, while showing low propensity to induce resistance. Both peptides feature a branched lipid tail on the N-terminal residue, which for brevicidine is chiral. Here, we report the synthesis and biological evaluation of a library of brevicidine and laterocidine analogues wherein the N-terminal lipid is replaced with linear achiral fatty acids. Optimal lipid chain lengths were determined and new analogues with strong activity against colistin-resistant E. coli produced.

18.
Chem Sci ; 13(12): 3563-3570, 2022 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-35432860

RESUMEN

Brevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, and a lipidated N-terminus, these lipopeptides exhibit potent and selective activity against Gram-negative pathogens, including polymyxin-resistant isolates. Given the low amounts of brevicidine and laterocidine accessible by fermentation of the producing microorganisms, synthetic routes to these lipopeptides present an attractive alternative. We here report the convenient solid-phase syntheses of both brevicidine and laterocidine and confirm their potent anti-Gram-negative activities. The synthetic routes developed also provide convenient access to novel structural analogues of both brevicidine and laterocidine that display improved hydrolytic stability while maintaining potent antibacterial activity in both in vitro assays and in vivo infection models.

19.
J Am Chem Soc ; 133(36): 14216-9, 2011 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-21848315

RESUMEN

Lantibiotics are antimicrobial peptides produced by bacteria. Some are employed for food preservation, whereas others have therapeutic potential due to their activity against organisms resistant to current antibiotics. They are ribosomally synthesized and posttranslationally modified by dehydration of serine and threonine residues followed by attack of thiols of cysteines to form monosulfide lanthionine and methyllanthionine rings, respectively. Chemical synthesis of peptide analogues is a powerful method to verify stereochemistry and access structure-activity relationships. However, solid supported synthesis of lantibiotics has been difficult due to problems in generating lanthionines and methyllanthionines with orthogonal protection and good stereochemical control. We report the solid-phase syntheses of both peptides of a two-component lantibiotic, lacticin 3147. Both successive and interlocking ring systems were synthesized on-resin, thereby providing a general methodology for this family of natural products.


Asunto(s)
Bacteriocinas/síntesis química , Secuencia de Aminoácidos , Bacteriocinas/química , Datos de Secuencia Molecular , Relación Estructura-Actividad
20.
RSC Med Chem ; 12(4): 538-551, 2021 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-34041489

RESUMEN

Tridecaptins are a re-emerging class of non-ribosomal antibacterial peptides (NRAPs) with potent activity against highly problematic strains of Gram-negative bacteria. An intricate mode of action has been reported to explain the bactericidal activity of these NRAPs, wherein they bind selectivity to the Gram-negative version of the peptidoglycan precursor lipid II on the outer leaflet of the inner membrane and disrupt the proton-motive force. Tridecaptins are highly amenable to synthetic modification owing to their linear structure, therefore, various synthetic analogues have been reported, several of which have enhanced antimicrobial activity, reduced cost of synthesis and/or improved stability towards d-peptidase mediated hydrolysis. It has also been demonstrated that unacylated tridecaptins can act synergistically with clinically relevant antibiotics by sensitizing the outer membrane. This review will summarize past literature on the development/discovery of novel tridecaptin analogues (up until the end of 2020), some of which may be useful therapeutic agents to treat insidious Gram-negative bacterial infections.

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