Noncovalent interactions involving sulfur atoms play essential roles in protein structure and function by significantly contributing to protein stability, folding, and biological activity. Sulfur is a highly polarizable atom that can participate in many types of noncovalent interactions including hydrogen bonding, sulfur-π interactions, and S-lone pair interactions, but the impact of these sulfur-based interactions on molecular recognition and drug design is still often underappreciated. Here, we examine, using quantum chemical calculations, the roles of sulfur-based noncovalent interactions in complex naturally occurring molecules representative of thiopeptide antibiotics: glycothiohexide α and its close structural analogue nocathiacin I. While donor-acceptor orbital interactions make only very small contributions, electrostatic and dispersion contributions are predicted to be significant in many cases. In pursuit of understanding the magnitudes and nature of these noncovalent interactions, we made potential structural modifications that could significantly expand the chemical space of effective thiopeptide antibiotics.

22 Apr 2022·Journal of Natural ProductsQ2 · BIOLOGY

Nocathiacin, Thiazomycin, and Polar Analogs Are Highly Effective Agents against Toxigenic Clostridioides difficile

Q2 · BIOLOGY

Review

Author: Kramer, Susanne ; Lipari, Phillip ; Singh, Sheo B. ; Liu, Gongjie ; Polishook, Jon D. ; Xu, Libo ; Miesel, Lynn ; Li, Fangbio ; Liang, Lianzhu ; Flattery, Amy M. ; Lan, Jing

Clostridioides difficile is a commensal Gram-positive gut bacterium that causes C. difficile-associated diarrhea. Currently available antibacterial therapeutic treatment options are effective except for the repeated recurrences significantly burdening the health care system and causing mortality. The development of new therapeutic modalities including new effective antibiotics with a low rate of recurrence has been unpredictive and exceedingly challenging, requiring continued profiling of many new classes of antibiotics. Nocathiacins and thiazomycins are a class of thiazolyl peptides exhibiting potent and selective broad-spectrum Gram-positive activity including activity against the anaerobe C. difficile. These compounds showed MIC values of 0.015-0.06 μg/mL against C. difficile with more than 100-200-fold selectivity versus commensurate Gram-negative Bacteroides fragilis. Nocathiacin I and one of its analogs exhibited potent in vivo efficacy in the gold-standard hamster model of C. difficile infection, providing 100% protection in this lethal model at 6.25 mg/kg orally twice daily. The efficacy was corroborated by robust reduction of cecum C. difficile burden and proportionate exposure of the compounds in the cecum contents without any systemic absorption. In this paper, details of the results of in vitro, in vivo, pharmacodynamics, and pharmacokinetic studies have been described.

18 Feb 2022·ACS Chemical BiologyQ2 · BIOLOGY

Rational Approach to Identify RNA Targets of Natural Products Enables Identification of Nocathiacin as an Inhibitor of an Oncogenic RNA

Q2 · BIOLOGY

Article

Author: Adibekian, Alexander ; Teijaro, Christiana N. ; Zhang, Peiyuan ; Shen, Ben ; Ye, Fei ; Suresh, Blessy M. ; Yang, Dong ; Crynen, Gogce ; Disney, Matthew D. ; Abegg, Daniel ; Yan, Wei ; Haniff, Hafeez S.

The discovery of biofunctional natural products (NPs) has relied on the phenotypic screening of extracts and subsequent laborious work to dereplicate active NPs and define cellular targets. Herein, NPs present as crude extracts, partially purified fractions, and pure compounds were screened directly against molecular target libraries of RNA structural motifs in a library-versus-library fashion. We identified 21 hits with affinity for RNA, including one pure NP, nocathiacin I (NOC-I). The resultant data set of NOC-I-RNA fold interactions was mapped to the human transcriptome to define potential bioactive interactions. Interestingly, one of NOC-I's most preferred RNA folds is present in the nuclease processing site in the oncogenic, noncoding microRNA-18a, which NOC-I binds with low micromolar affinity. This affinity for the RNA translates into the selective inhibition of its nuclease processing in vitro and in prostate cancer cells, in which NOC-I also triggers apoptosis. In principle, adaptation of this combination of experimental and predictive approaches to dereplicate NPs from the other hits (extracts and partially purified fractions) could fundamentally transform the current paradigm and accelerate the discovery of NPs that bind RNA and their simultaneous correlation to biological targets.

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Indication	Highest Phase	Country/Location	Organization	Date
Gram-Positive Bacterial Infections	Preclinical	United States	Achillion Pharmaceuticals, Inc.	03 Jun 2004

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