In This Issue pubs.acs.org/journal/aidcbc
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NEW TARGETS FOR ANTIPARASITIC DRUG DEVELOPMENT
whole cell activity assays, cell-based targocil antagonist assays to enrich for UppS inhibitors, and biochemical assays for UppS activity to arrive at UppS inhibitors. The strategy is designed not only to overcome but also to exploit common pitfalls that have derailed many antimicrobial campaigns. The combination of cutting edge technologies with more traditional approaches presents a novel approach to characterizing the resulting UppS inhibitors of interest. Ultimately, the UppS inhibitors reported here will serve as useful chemical probes in screening assays for synergistic combinations of molecules targeting cell-wall biosynthesis in pathogenic bacteria.
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A major challenge in the development of antiparasitic agents is the identification of essential druggable targets in the parasite that are absent in their eukaryotic host. Trypanosoma brucei, the causative agent of human African trypanosomiasis, has a transferrin receptor that lacks sequence similarity to the human transferrin receptor. The differences in these receptors reflect major differences in transferrin endocytosis pathways between the parasite and host, suggesting that transferrin endocytosis may be a suitable novel target for antitrypanosome drug development. In the work presented on the cover of this month’s issue, Guyett et al. (DOI: 10.1021/acsinfecdis.6b00077) use a multifaceted approach to study trypanosome glycogen synthase kinase 3β (GSK3β) and provide evidence that GSK3β selectively stimulates the endocytosis of transferrin in this parasite. The authors use both genetic and chemical probes to delineate the role of GSK3β in trypanosome biology and conduct endocytosis assays to identify a small-molecule inhibitor of GSK3β with the ability to phenocopy a GSK3β knockdown. Furthermore, the authors exploit their new-found understanding of the role of GSK3β in trypanosome biology to identify new chemotypes that may be used as hits for antitrypanosome drug discovery.
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Clostridium dif f icile is the leading cause of antibiotic-associated nosocomial infections in the United States, with particularly burdensome healthcare costs for acute care facilities. In recent years, the overall incidence of C. dif f icile infections has surged dramatically because of the emergence of hypervirulent strains, which are characterized by increased toxin production and fluoroquinolone resistance. Although C. dif ficile responds to current treatment options, including metronidazole, vancomycin, and fidaxomicin, disease recurrence continues to be a significant problem, and a need for alternative targets and strategies persists. C. dif f icile expresses a surface layer that helps to maintain its structural integrity and aids in host cell adherence and colonization. The cysteine protease Cwp84 is responsible for the maturation of the surface layer and was also shown to cleave extracellular matrix components fibronectin, laminin, and vitronectin. In this issue, Gooyit et al. (DOI: 10.1021/ acsinfecdis.6b00061) engineer a FRET-based screening assay useful for the characterization of Cwp84 inhibitors and use this to identify substrate mimetics. Through the synthesis of focused libraries, they successfully identify novel inhibitors that are 100 times more potent than any previously described compounds and show that the treatment of whole cells of C. dif f icile with these inhibitors blocks the processing of endogenous SlpA.
INNOVATIVE APPROACH TO IDENTIFYING UppS INHIBITORS
Undecaprenyl-pyrophosphate synthase (UppS) is a promising cell-wall-associated antimicrobial target that benefits from all of the features that have driven the success of historically analogous targets; namely, it is conserved, essential, unique to prokaryotes, and is an accessible potential drug target. The ACS Editor’s Choice article by Czarny et al. (DOI: 10.1021/acsinfecdis.6b00044) introduces a small-molecule antimicrobial screening paradigm for the enrichment and prioritization of UppS inhibitors. Here, the authors blend © 2016 American Chemical Society
INVESTIGATING ALTERNATIVE DRUG TARGETS IN C. dif ficile
Received: June 24, 2016 Published: July 8, 2016 452
DOI: 10.1021/acsinfecdis.6b00119 ACS Infect. Dis. 2016, 2, 452−452
