Antibacterial Optimization of 4-Aminothiazolyl Analogues of the Natural Product GE2270 A: Identification of the Cycloalkylcarboxylic Acids

LaMarche, Matthew J.; Leeds, Jennifer A.; Amaral, Kerri; Brewer, Jason; Bushell, Simon M.; Dewhurst, Janetta; Dzink-Fox, JoAnne; Gangl, Eric; Goldovitz, Julie; Jain, Akash; Mullin, Steve; Neckermann, Georg; Osborne, Colin; Palestrant, Deborah; Patane, Michael A.; Rann, Elin M.; Sachdeva, Meena; Shao, Jun Peng; Tiamfook, Stacey; Whitehead, Lewis; Yu, Donghui

doi:10.1021/jm200938f

Cited by 38 publications

(49 citation statements)

References 12 publications

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“…Although the in vitro activity of this compound was shown to be excellent against MRSA, VRE, and streptococci, poor aqueous solubility prevented further development 83. Two derivatives are currently being investigated.…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

“…The 4‐aminothiazolyl moiety was chosen as a starting point and a wide variety of amines and acids linked via different spacers were synthesized 83, 84, 85. Guided by co‐crystal structures with EF‐Tu, this search led to the discovery of two potent analogues with cyclohexylcarboxylic acid side chains residing in proximity to the Arg223 residue of EF‐Tu.…”

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%

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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“…Based on the crystal structure of the prokaryotic chaperone elongation factor Tu (EF-Tu), LaMarche and co-workers expanded the analogue library of G1 utilizing amide and carbamate linkages [113]. Focusing on the substitution of the 4-aminothiazole macrocyclic appendage, a variety of termini groups, involving trifluoroacetate, carboxylic acid, carboxy ester, phosphoric acid, carboxamide, alcohol, free or dimethyl amine (G10-G17, Table 16) was employed to improve cellular antibacterial activity and to increase intrinsic aqueous solubility of the molecule.…”

Section: Compmentioning

confidence: 99%

Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

Wahyudi

McAlpine

2015

Bioorganic Chemistry

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“…From all combinations of the differences, a phylogenetic tree was written by the unweighted pair group method with arithmetic mean [34] Table 1. However, because of uncertain functions, we excluded the following ions or molecules; sodium ion, acetate ion, sulfate ion, ammonium ion, sugar (sucrose), di(hydroxyethyl)ether, glyoxylic acid, 5-bromofuran-2-carboxylic acid, β-mercaptoethanol and water [37][38][39][40][41][42][43].…”

Section: Data Collectionmentioning

confidence: 99%

Protein Functional Site Prediction Using a Conservative Grade and a Proximate Grade

Kondo¹,

Miyazaki²

2015

J Data Mining Genomics Proteomics

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So far, in order to predict important sites of a protein, many computational methods have been developed. In the era of big-data, it is required for improvements and sophistication of existing methods by integrating sequence data in the structural data. In this paper, we aim at two things: improving sequence-based methods and developing a new method using both sequence and structural data. Therefore, we developed an originally modified evolutionary trace method, in which we defined conservative grades calculated from a given multiple sequence alignment and a proximate grade in order to evaluate predicted active sites from a viewpoint of protein-ion, protein-ligand, protein-nucleic acid, proteinprotein interaction by use of three-dimensional structures. In other words, the proximate grade also can evaluate an amino acid residue. When we applied our method to translation elongation factor Tu/1A proteins, it showed that the conservative grades are evaluated accurately by the proximate grade. Consequently, our idea indicated two advantages. One is that we can take into account various cocrystal structures for evaluation. Another one is that, by calculating the fitness between the given conservative grade and the proximate grade, we can select the best conservative grade. Journal of Data Mining in Genomics & Proteomics Mapping by a character typeIn this section, we define mathematical formulation of a mapping by similarity of the amino acid symbols on i M . Let Where T=1,2,…N.As shown in Figure 1B Where τ is a threshold of ( )Where is a multiset which is separated at time point . For example, ;Let A denote a field of sets of amino acid symbols anddenote a field of sets of gaps in 1 M . For example, A is definable asand t G is definable aswhere G is a number of gaps.h M be represented as following four definitions:whereA G is a number of sets in ∪ i A G and , log , Where max , min S , ( ) , S l l and ( ) , S l m are the maximum, the minimum, a diagonal element and an off-diagonal element in an amino acid substitution matrix, respectively, andwhere l is a weight of sequence l . Mapping by a coordinate type Let denote a set of real numbers and there be , ,...,M denote a set of residues in i M denote a set of residues in i M and Materials and Methods Data collectionIn UniProtKB/Swiss-Prot release 2015_01 [24], entries which are annotated as 'Classic translation factor GTPase family. EF-Tu/EF-1A subfamily', do not include 'X' in the sequence and are not a fragment were 984 entries. In the PDB, entries which are referenced from above 984 entries and are determined by X-ray crystallography were 68 entries. 14 entries were excluded because of binding an immunoprotein [25] and forming a chimeric protein [26][27][28][29]. Consequently, as shown in Table 1, 54 entries including 103 chains were retained. Computations of f 1 and f 2As N=984 and K=103 in Figure 2, the sequences were aligned by the Correlations between f 1 and f 2 Let ( )denote a subset of non-negative real numbers and a set of ( ) .... Let j t denote a...

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Antibacterial Optimization of 4-Aminothiazolyl Analogues of the Natural Product GE2270 A: Identification of the Cycloalkylcarboxylic Acids

Cited by 38 publications

References 12 publications

Targeting Antibiotic Resistance

Targeting Antibiotic Resistance

Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

Protein Functional Site Prediction Using a Conservative Grade and a Proximate Grade

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