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Teixobactin

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https://www.readbyqxmd.com/read/29029900/teixobactin-as-a-scaffold-for-unlimited-new-antimicrobial-peptides-sar-study
#1
Shimaa A H Abdel Monaim, Yahya E Jad, Ayman El-Faham, Beatriz G de la Torre, Fernando Albericio
It looks that a new era of antimicrobial peptides (AMPs) started with the discovery of teixobactin, which is a "head to side-chain" cyclodepsipeptide. It was isolated from a soil gram-negative b-proteobacteria by means of a revolutionary technique. Since there, several groups have developed synthetic strategies for efficient synthesis of this peptide and its analogues as well. Herein, all chemistries reported as well as the biological activity of the analogues are analyzed. Finally, some inputs regarding new trends for the next generation of analogues are discussed...
September 30, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28993827/synthesis-and-biological-evaluation-of-novel-teixobactin-analogues
#2
Christian E Schumacher, Paul W R Harris, Xiao-Bo Ding, Bernard Krause, Tom H Wright, Gregory M Cook, Daniel P Furkert, Margaret A Brimble
The cyclic depsipeptide, teixobactin, possesses promising activity against a range of antimicrobial-resistant (AMR) pathogenic bacteria, including Staphylococcus aureus and Mycobacterium tuberculosis. Teixobactin contains a number of non-canonical residues, including the synthetically challenging amino acid, l-allo-enduracididine, complicating clinical application of this peptide. Herein, we report the synthesis of six analogues of teixobactin, in which the non-canonical l-allo-enduracididine amino acid is replaced by isosteric, commercially available Fmoc-amino acid building blocks...
October 25, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28991382/chemistry-and-biology-of-teixobactin
#3
Qi Zhang
Bacterial resistance to existing drugs is becoming a serious public health issue, urging extensive search for new antibiotics. Teixobactin, a cyclic depsipeptide discovered in a screen of uncultured bacteria, shows potent activity against all the tested Gram-positive bacteria. Remarkably, no teixobactin-resistant bacterial strain has been obtained despite extensive efforts, highlighting the great potential of teixobactin as a lead compound in fighting against antimicrobial resistance (AMR). This review summarizes recent progresses in the understanding of many aspects of teixobactin, including chemical structure, biological activity, biosynthetic pathway, and mode of action...
October 9, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28969532/binding-site-and-potency-prediction-of-teixobactin-and-other-lipid-ii-ligands-by-statistical-base-scoring-of-conformational-space-maps
#4
Claudiu N Lungu, Mircea V Diudea
A receptor binding pocket may be occupied by a ligand in various plausible conformations, among which only few ones are energetically related to a biological activity in the physiological efficiency domain. This paper reports the mapping of the conformational space of Lipid II in its interaction with Teixobactin and other Lipid II ligands. Statistical analysis of the resulted data enabled the selection of most favorable ligands and receptor conformations; a score was generated for ordering the ligand-receptor complexes, according to the their lowest energy and in correlation with the efficiency of their biological function...
September 26, 2017: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/28967925/alanine-scan-reveals-modifiable-residues-in-teixobactin
#5
K H Chen, S P Le, X Han, J M Frias, J S Nowick
An alanine scan of Lys10-teixobactin reveals that a cationic residue at position 10 is not necessary for antibiotic activity and that position 3 tolerates substitution without loss of activity. An unexpected correlation between poor aqueous solubility and better antibiotic activity of the teixobactin analogues is observed.
October 12, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28956840/investigation-of-the-n-terminus-amino-function-of-arg10-teixobactin
#6
Shimaa A H Abdel Monaim, Sikabwe Noki, Estelle J Ramchuran, Ayman El-Faham, Fernando Albericio, Beatriz G de la Torre
Teixobactin is a recently described antimicrobial peptide that shows high activity against gram-positive bacteria as well as mycobacterium tuberculosis. Due to both its structure as a head-to-side chain cyclodepsipeptide and its activity, it has attracted the attention of several research groups. In this regard, a large number of analogs with substitutions in both the cycle and the tail has been described. Here, we report the contribution of the N-terminus residue, N-Me-d-Phe, to the activity of Arg10-teixobactin...
September 28, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28795806/converting-teixobactin-into-a-cationic-antimicrobial-peptide-amp
#7
Shimaa A H Abdel Monaim, Estelle J Ramchuran, Ayman El-Faham, Fernando Albericio, Beatriz G de la Torre
Teixobactin is a head to side chain cyclodepsipeptide that contains two positive charges. One is found in the cycle, as a result of the presence of the guanidino-unusual amino acid L-allo-End, while the other is at the N-terminal. Here we introduce 26 new Teixobactin analogues with an increasing number of positive charges. In an attempt to fine-tune the biological activity of Teixobactin, we examined the effect of cationicity on the SAR of these analogues. The maximum number of positive charges to maintain the activity are three to four...
September 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28770988/teixobactin-and-its-analogues-a-new-hope-in-antibiotic-discovery
#8
William D Fiers, Mark Craighead, Ishwar Singh
Increasing bacterial resistance against current antibiotics and lack of new molecules to combat bacterial resistance are key challenges to global health. There is, therefore, a continuing need to develop new antibiotics. Teixobactin, a cyclic undecapeptide, displays excellent antibacterial activities against a range of pathogenic bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis. Interestingly, it operates by multiple modes of actions and is bactericidal toward S...
October 13, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28650495/syntheses-of-potent-teixobactin-analogues-against-methicillin-resistant-staphylococcus-aureus-mrsa-through-the-replacement-of-l-allo-enduracididine-with-its-isosteres
#9
Anish Parmar, Abhishek Iyer, Daniel G Lloyd, Charlotte S Vincent, Stephen H Prior, Annemieke Madder, Edward J Taylor, Ishwar Singh
The recently discovered cyclic depsipeptide, teixobactin, is a highly potent antibiotic against multi-drug resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and Mycobaterium tuberculosis. It comprises of 4 D amino acids and a rare l-allo-enduracididine amino acid. The synthesis of a properly protected l-allo-enduracididine amino acid and its incorporation into teixobactin is time consuming, synthetically challenging and low yielding and is therefore a major bottleneck in the development of potent analogues of teixobactin...
July 6, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28495382/synthesis-and-structure-activity-relationship-of-teixobactin-analogues-via-convergent-ser-ligation
#10
Kang Jin, Kathy Hiu Laam Po, Shengxi Wang, Jonathan Avraham Reuven, Chi Nga Wai, Ho Ting Lau, Ting Ho Chan, Sheng Chen, Xuechen Li
Convergent Ser/Thr ligation has been used to prepare a series of teixobactin analogues (28 in total) to establish a structure-activity relationship of teixobactin. anti-bacterial evaluations of these synthetic analogues have revealed the critical amino acid residues and the sites tolerable of modifications. These studies will shed lights on the further development of teixobactin analogues with improved antibacterial activities.
September 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28217800/x-ray-crystallographic-structure-of-a-teixobactin-analogue-reveals-key-interactions-of-the-teixobactin-pharmacophore
#11
H Yang, D R Du Bois, J W Ziller, J S Nowick
The X-ray crystallographic structure of a truncated teixobactin analogue reveals hydrogen-bonding and hydrophobic interactions and a cavity that binds a chloride anion. Minimum inhibitory concentration (MIC) assays against Gram-positive bacteria correlate the observed structure with antibiotic activity.
February 28, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28209400/multidrug-resistant-enterococcal-infections-new-compounds-novel-antimicrobial-therapies
#12
REVIEW
Roel M van Harten, Rob J L Willems, Nathaniel I Martin, Antoni P A Hendrickx
Over the past two decades infections due to antibiotic-resistant bacteria have escalated world-wide, affecting patient morbidity, mortality, and health care costs. Among these bacteria, Enterococcus faecium and Enterococcus faecalis represent opportunistic nosocomial pathogens that cause difficult-to-treat infections because of intrinsic and acquired resistance to a plethora of antibiotics. In recent years, a number of novel antimicrobial compound classes have been discovered and developed that target Gram-positive bacteria, including E...
June 2017: Trends in Microbiology
https://www.readbyqxmd.com/read/28124045/defining-the-molecular-structure-of-teixobactin-analogues-and-understanding-their-role-in-antibacterial-activities
#13
Anish Parmar, Stephen H Prior, Abhishek Iyer, Charlotte S Vincent, Dorien Van Lysebetten, Eefjan Breukink, Annemieke Madder, Edward J Taylor, Ishwar Singh
The discovery of the highly potent antibiotic teixobactin, which kills the bacteria without any detectable resistance, has stimulated interest in its structure-activity relationship. However, a molecular structure-activity relationship has not been established so far for teixobactin. Moreover, the importance of the individual amino acids in terms of their l/d configuration and their contribution to the molecular structure and biological activity are still unknown. For the first time, we have defined the molecular structure of seven teixobactin analogues through the variation of the d/l configuration of its key residues, namely N-Me-d-Phe, d-Gln, d-allo-Ile and d-Thr...
January 26, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/27704270/new-structural-templates-for-clinically-validated-and-novel-targets-in-antimicrobial-drug-research-and-development
#14
REVIEW
Philipp Klahn, Mark Brönstrup
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...
2016: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/27550357/dual-targeting-of-cell-wall-precursors-by-teixobactin-leads-to-cell-lysis
#15
Tomoyuki Homma, Austin Nuxoll, Autumn Brown Gandt, Patrick Ebner, Ina Engels, Tanja Schneider, Friedrich Götz, Kim Lewis, Brian P Conlon
Teixobactin represents the first member of a newly discovered class of antibiotics that act through inhibition of cell wall synthesis. Teixobactin binds multiple bactoprenol-coupled cell wall precursors, inhibiting both peptidoglycan and teichoic acid synthesis. Here, we show that the impressive bactericidal activity of teixobactin is due to the synergistic inhibition of both targets, resulting in cell wall damage, delocalization of autolysins, and subsequent cell lysis. We also find that teixobactin does not bind mature peptidoglycan, further increasing its activity at high cell densities and against vancomycin-intermediate Staphylococcus aureus (VISA) isolates with thickened peptidoglycan layers...
November 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27484680/total-synthesis-of-teixobactin
#16
Kang Jin, Iek Hou Sam, Kathy Hiu Laam Po, Du'an Lin, Ebrahim H Ghazvini Zadeh, Sheng Chen, Yu Yuan, Xuechen Li
To cope with the global bacterial multidrug resistance, scientific communities have devoted significant efforts to develop novel antibiotics, particularly those with new modes of actions. Teixobactin, recently isolated from uncultured bacteria, is considered as a promising first-in-class drug candidate for clinical development. Herein, we report its total synthesis by a highly convergent Ser ligation approach and this strategy allows us to prepare several analogues of the natural product.
August 3, 2016: Nature Communications
https://www.readbyqxmd.com/read/27388768/new-found-hope-for-antibiotic-discovery-lipid-ii-inhibitors
#17
REVIEW
Vivian Ng, Weng C Chan
Research into antibacterial agents has recently gathered pace in light of the disturbing crisis of antimicrobial resistance. The development of modern tools offers the opportunity of reviving the fallen era of antibacterial discovery through uncovering novel lead compounds that target vital bacterial cell components, such as lipid II. This paper provides a summary of the role of lipid II as well as an overview and insight into the structural features of macrocyclic peptides that inhibit this bacterial cell wall component...
August 26, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27232661/elucidation-of-the-teixobactin-pharmacophore
#18
Hyunjun Yang, Kevin H Chen, James S Nowick
This paper elucidates the teixobactin pharmacophore by comparing the arginine analogue of teixobactin Arg10-teixobactin to seven homologues with varying structure and stereochemistry. The roles of the guanidinium group at position 10, the stereochemistry of the macrolactone ring, and the "tail" comprising residues 1-5 are investigated. The guanidinium group is not necessary for activity; Lys10-teixobactin is more active than Arg10-teixobactin against Gram-positive bacteria in minimum inhibitory concentration (MIC) assays...
July 15, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27191730/total-synthesis-of-teixobactin
#19
Andrew M Giltrap, Luke J Dowman, Gayathri Nagalingam, Jessica L Ochoa, Roger G Linington, Warwick J Britton, Richard J Payne
The first total synthesis of the cyclic depsipeptide natural product teixobactin is described. Synthesis was achieved by solid-phase peptide synthesis, incorporating the unusual l-allo-enduracididine as a suitably protected synthetic cassette and employing a key on-resin esterification and solution-phase macrolactamization. The synthetic natural product was shown to possess potent antibacterial activity against a range of Gram-positive pathogenic bacteria, including a virulent strain of Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus (MRSA)...
June 3, 2016: Organic Letters
https://www.readbyqxmd.com/read/27168676/combating-tuberculosis-infection-a-forbidding-challenge
#20
REVIEW
Tejal Rawal, Shital Butani
After 50 years drought, several drugs are looming from the pipeline to combat tuberculosis. They will serve as a boon to the field that has been burdened with primitive, inadequate treatments and drug-resistant bacterial strains. From the decades, due to lack of interest and resources, the field has suffered a lot. Learning from the flaws, scientists have renovated their approaches to the finding of new antitubercular drugs. The first line drugs take about six months or more for the entire treatment. The second line remedy for resistant-tuberculosis requires daily injections which carry severe side effects...
January 2016: Indian Journal of Pharmaceutical Sciences
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