Successful application of serum shift prediction models to the design of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV with improved in vivo efficacy

Perola, Emanuele; Stamos, Dean; Grillot, Anne‐Laure; Ronkin, Steven; Wang, Tiansheng; LeTiran, Arnaud; Tang, Qing; Deininger, David D.; Liao, Yusheng; Tian, Shi‐Kai; Drumm, Joseph E.; Nicolau, David P.; Tessier, Pamela R.; Mani, Nagraj; Grossman, Trudy H.; Charifson, Paul S.

doi:10.1016/j.bmcl.2014.03.022

Cited by 8 publications

(10 citation statements)

References 16 publications

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“…In some cases the shift is high enough that the effect of adding 2% HSA rendered the compound inactive against the pathogen of interest. The role of hydrophobicity and plasma protein binding has been discussed in a recent paper by a group at Vertex, with a conclusion that keeping clogP low (<2.1) and PSA high (>120) resulted in shifts <16-fold within a series of topoisomerase inhibitors . We extended this analysis to all classes of antibacterial compounds presented earlier in the text in Figure .…”

Section: Effect Of Hydrophobicity On Plasma Protein Binding and Plasm...mentioning

confidence: 93%

“…The role of hydrophobicity and plasma protein binding has been discussed in a recent paper by a group at Vertex, with a conclusion that keeping clogP low (<2.1) and PSA high (>120) resulted in shifts <16-fold within a series of topoisomerase inhibitors. 18 We extended this analysis to all classes of antibacterial compounds presented earlier in the text in Figure 1. Our results indicated that clogD was a very good predictor of serum shifting with some exceptions (Figure 11a).…”

Section: Activesmentioning

confidence: 99%

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Trends and Exceptions of Physical Properties on Antibacterial Activity for Gram-Positive and Gram-Negative Pathogens

et al. 2014

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To better understand the difficulties surrounding the identification of novel antibacterial compounds from corporate screening collections, physical properties of ∼3200 antibacterial project compounds with whole cell activity against Gram-negative or Gram-positive pathogens were profiled and compared to actives found from high throughput (HTS) screens conducted on both biochemical and phenotypic bacterial targets. The output from 23 antibacterial HTS screens illustrated that when compared to the properties of the antibacterial project compounds, the HTS actives were significantly more hydrophobic than antibacterial project compounds (typically 2-4 log units higher), and furthermore, for 14/23 HTS screens, the average clogD was higher than the screening collection average (screening collection clogD = 2.45). It was found that the consequences of this were the following: (a) lead identification programs often further gained hydrophobic character with increased biochemical potency, making the separation even larger between the physicochemical properties of known antibacterial agents and the HTS active starting point, (b) the probability of plasma protein binding and cytotoxicity are often increased, and (c) cell-based activity in Gram-negative bacteria was severely limited or, if present, demonstrated significant efflux. Our analysis illustrated that compounds least susceptible to efflux were those which were highly polar and small in MW or very large and typically zwitterionic. Hydrophobicity was often the dominant driver for HTS actives but, more often than not, precluded whole cell antibacterial activity. However, simply designing polar compounds was not sufficient for antibacterial activity and pointed to a lack of understanding of complex and specific bacterial penetration mechanisms.

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Section: Effect Of Hydrophobicity On Plasma Protein Binding and Plasm...mentioning

confidence: 93%

Section: Activesmentioning

confidence: 99%

Trends and Exceptions of Physical Properties on Antibacterial Activity for Gram-Positive and Gram-Negative Pathogens

et al. 2014

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“…Figure 14. The two subclasses of benzimidazole ureas, with their optimal properties for reduced serum shift [78][79][80].…”

Section: Inhibitors Focused On Mycobacterium Tuberculosis Dna Gyrasementioning

confidence: 99%

“…Differential scanning fluorimetry also showed better thermal stabilization of the protein-ligand complex, with a Tm shift of 2.5 °C.Preclinical Optimization strategiesAs several compounds entered into the more mature stages of preclinical development, both their activities and their other properties were optimised. Perola et al from Vertex[78] studied the role of plasma and tissue protein binding on the activities of GyrB inhibitors. Studies of the benzimidazole ureas showed 95% protein binding and 16-fold to 128-fold serum shifts (i.e., ratio between MIC in the presence and absence of 50% human serum).…”

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confidence: 99%

Recent Progress in the Discovery and Development of DNA Gyrase B Inhibitors

2018

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New antibacterials that modulate less explored targets are needed to fight the emerging bacterial resistance. DNA gyrase and topoisomerase IV are attractive targets in this search. These are both type II topoisomerases that can cleave both DNA strands, and can thus alter DNA topology during replication or similar processes. Currently, there are no ATP-competitive inhibitors of these two enzymes on the market, as the only aminocoumarin representative, novobiocin, was withdrawn due to safety concerns. The search for novel ATP-competitive inhibitors is a focus of ongoing industrial and academical research. This review summarizes the recent efforts in the design, synthesis and evaluation of GyrB/ParE inhibitors. The various approaches to achieve improved antibacterial activities are described, with particular reference to Gram-negative bacteria.

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“…109 However, the activities of 104 and other analogs against C. dif ficile have not been reported. The Vertex library of aminobenzimidazoles (>330 compounds) 110 prepared could be reinvestigated to potentially identify alternative lead compounds with potent, more selective activity against C. dif f icile and poor oral availability. Dual action benzothiazole ethyl urea based compounds have been explored by Biota, inhibiting the DNA gyrase GyrB and topoisomerase IV ParE ATPase.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Clostridium difficile Drug Pipeline: Challenges in Discovery and Development of New Agents

et al. 2015

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In the past decade Clostridium difficile has become a bacterial pathogen of global significance. Epidemic strains have spread throughout hospitals, while community acquired infections and other sources ensure a constant inoculation of spores into hospitals. In response to the increasing medical burden, a new C. difficile antibiotic, fidaxomicin, was approved in 2011 for the treatment of C. difficile-associated diarrhea. Rudimentary fecal transplants are also being trialed as effective treatments. Despite these advances, therapies that are more effective against C. difficile spores and less damaging to the resident gastrointestinal microbiome and that reduce recurrent disease are still desperately needed. However, bringing a new treatment for C. difficile infection to market involves particular challenges. This review covers the current drug discovery pipeline, including both small molecule and biologic therapies, and highlights the challenges associated with in vitro and in vivo models of C. difficile infection for drug screening and lead optimization.

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Successful application of serum shift prediction models to the design of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV with improved in vivo efficacy

Cited by 8 publications

References 16 publications

Trends and Exceptions of Physical Properties on Antibacterial Activity for Gram-Positive and Gram-Negative Pathogens

Trends and Exceptions of Physical Properties on Antibacterial Activity for Gram-Positive and Gram-Negative Pathogens

Recent Progress in the Discovery and Development of DNA Gyrase B Inhibitors

Clostridium difficile Drug Pipeline: Challenges in Discovery and Development of New Agents

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