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Vivian Ng, Sarah A Kuehne, Weng Chan
Teixobactin, a recently discovered depsipeptide that binds to bacterial lipid II and lipid III, provides a promising molecular scaffold for the design of new antimicrobials. Herein, we describe the synthesis and antimicrobial evaluation of systematically modified teixobactin analogues. The replacement of Ile11 residue with aliphatic isosteres, the modification of the guanidino group at residue 10 and the introduction of a rigidifying residue, dehydroamino acid into the macrocyclic ring generated useful structure-activity information...
May 9, 2018: Chemistry: a European Journal
Yu Zong, Xiuyun Sun, Hongying Gao, Kirsten J Meyer, Kim Lewis, Yu Rao
Teixobactin, targeting lipid II, represents a new class of antibiotics with novel structures and has excellent activity against Gram-positive pathogens. We developed a new convergent method to synthesize a series of teixobactin analogues and explored structure-activity relationships. We obtained equipotent and simplified teixobactin analogues, replacing the l- allo-enduracididine with lysine, substituting oxygen to nitrogen on threonine, and adding a phenyl group on the d-phenylalanine. On the basis of the antibacterial activities that resulted from corresponding modifications of the d-phenylalanine, we propose a hydrophobic interaction between lipid II and the N-terminal of teixobactin analogues, which we map out with our analogue 35...
April 13, 2018: Journal of Medicinal Chemistry
Anish Parmar, Abhishek Iyer, Stephen H Prior, Daniel G Lloyd, Eunice Tze Leng Goh, Charlotte S Vincent, Timea Palmai-Pallag, Csanad Z Bachrati, Eefjan Breukink, Annemieke Madder, Rajamani Lakshminarayanan, Edward J Taylor, Ishwar Singh
Teixobactin is a highly promising antibacterial depsipeptide consisting of four d-amino acids and a rare l- allo -enduracididine amino acid. l- allo -Enduracididine is reported to be important for the highly potent antibacterial activity of teixobactin. However, it is also a key limiting factor in the development of potent teixobactin analogues due to several synthetic challenges such as it is not commercially available, requires a multistep synthesis, long and repetitive couplings (16-30 hours). Due to all these challenges, the total synthesis of teixobactin is laborious and low yielding (3...
December 1, 2017: Chemical Science
Georgina C Girt, Amit Mahindra, Zaaima J H Al Jabri, Megan De Ste Croix, Marco R Oggioni, Andrew G Jamieson
A series of lipopeptidomimetics derived from teixobactin have been prepared that probe the role of residues (1-6) as a membrane anchor and the function of enduracididine. The most active compounds, with a farnesyl tail and End10 to Lys10 or Orn10 substitution have potent activity (MIC 8 μg mL-1 ) against S. aureus. These results pave the way for the synthesis of simple, cost-effective yet potent lipopeptidomimetic antimicrobials.
March 13, 2018: Chemical Communications: Chem Comm
Yong-Xin Li, Zheng Zhong, Peng Hou, Wei-Peng Zhang, Pei-Yuan Qian
Nonribosomal peptide antibiotics, including polymyxin, vancomycin, and teixobactin, most of which contain D-amino acids, are highly effective against multidrug-resistant bacteria. However, overusing antibiotics while ignoring the risk of resistance arising has inexorably led to widespread emergence of resistant bacteria. Therefore, elucidation of the emerging mechanisms of resistance to nonribosomal peptide antibiotics is critical to their implementation. Here we describe a networking-associated genome-mining platform for linking biosynthetic building blocks to resistance components associated with biosynthetic gene clusters...
April 2018: Nature Chemical Biology
Kang Jin, Kathy Hiu Laam Po, Wang Yeuk Kong, Chung Hei Lo, Chun Wah Lo, Ho Yin Lam, Amaya Sirinimal, Jonathan Avraham Reuven, Sheng Chen, Xuechen Li
Teixobactin is a structurally and mechanistically novel antimicrobial peptide with potent activities against Gram-positive pathogens. It contains l-allo-enduracididine (End) residue which is not readily accessible. In this report, we have used convergent Ser Ligation as the key step to prepare a series of teixobactin analogues with End being substituted with its non-isostere moieties. Among these analogues, compounds T16, T27 and T29 exhibited the best antimicrobial activities against different Gram-positive bacteria with MICs ranging from 0...
March 1, 2018: Bioorganic & Medicinal Chemistry
Anish Parmar, Rajamani Lakshminarayanan, Abhishek Iyer, Venkatesh Mayandi, Eunice Tze Leng Goh, Daniel G Lloyd, Madhavi Latha S Chalasani, Navin K Verma, Stephen H Prior, Roger W Beuerman, Annemieke Madder, Edward J Taylor, Ishwar Singh
The cyclic depsipeptide, teixobactin, kills a number of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and Mycobacterium tuberculosis without detectable resistance. To date, teixobactin is the only molecule in its class that has shown in vivo antibacterial efficacy. In this work, we designed and synthesized 10 new in vivo ready teixobactin analogues. These analogues showed highly potent antibacterial activities against Staphylococcus aureus, MRSA, and vancomycin-resistant enterococci (VRE) in vitro...
March 8, 2018: Journal of Medicinal Chemistry
Dhanaraju Mandalapu, Xinjian Ji, Jinfeng Chen, Chuchu Guo, Wan-Qiu Liu, Wei Ding, Jiahai Zhou, Qi Zhang
A chemoenzymatic approach for the synthesis of teixobactin analogues has been established by using the tandem thioesterase (TE) of the nonribosomal peptide synthase (NRPS) Txo2. We show that, unlike the closely related counterparts involved in lysobactin biosynthesis (in which the N-terminal TE is solely responsible for the lactonization reaction), the two teixobactin TE domains are functionally exchangeable and likely act synergistically, representing an unprecedented off-loading mechanism in NRPS enzymology...
January 31, 2018: Journal of Organic Chemistry
Ishwar Singh
Ishwar Singh speaks to Benjamin Walden, Commissioning Editor. Ishwar Singh is Senior Lecturer in biological chemistry at the School of Pharmacy, University of Lincoln. Prior to Lincoln, he had held many prestigious fellowships such as the Alexander von Humboldt fellowship, Germany; and Senior Research Fellowship, DANIDA, Denmark and CSIR, India. He is an organic chemist. He has developed bioconjugations for DNA, RNA and polymer modifications. He is currently leading research in novel antimicrobials based on rational design against clinically important resistant bacteria (such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, mycobacteria, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa), biologics delivery, peptides, sequence-selective DNA cross linking, nanoparticles modifications for drug delivery and diagnostic applications...
January 2018: Future Medicinal Chemistry
Yang Liu, Yaxin Liu, Mary B Chan-Park, Yuguang Mu
Teixobactin (TXB) is a newly discovered antibiotic targeting the bacterial cell wall precursor Lipid II (LII ). In the present work, four binding modes of TXB on LII were identified by a contact-map based clustering method. The highly flexible binary complex ensemble was generated by parallel tempering metadynamics simulation in a well-tempered ensemble (PTMetaD-WTE). In agreement with experimental findings, the pyrophosphate group and the attached first sugar subunit of LII are found to be the minimal motif for stable TXB binding...
December 8, 2017: Scientific Reports
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
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
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
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
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
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
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
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
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
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
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