Identification of Highly Specific Diversity-Oriented Synthesis-Derived Inhibitors of Clostridium difficile

Abstract

In 2013, the Centers for Disease Control highlighted Clostridium difficile as an urgent threat for antibiotic-resistant infections, in part due to the emergence of highly virulent fluoroquinolone-resistant strains. Limited therapeutic options currently exist, many of which result in disease relapse. We sought to identify molecules specifically targeting C. difficile in high-throughput screens of our diversity-oriented synthesis compound collection. We identified two scaffolds with apparently novel mechanisms of action that selectively target C. difficile while having little to no activity against other intestinal anaerobes; preliminary evidence suggests that compounds from one of these scaffolds target the glutamate racemase. In vivo efficacy data suggest that both compound series may provide lead optimization candidates.

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

“…In the meantime, the limitations of current compound libraries have been understood and contemporary approaches are being pursued to broaden the chemical space used for antibacterial screenings. New libraries are generated using combinatorial and diversity‐oriented synthesis or small‐molecule fragments . These libraries are mostly used for the targeted screening of purified proteins.…”

“…Application of these guidelines to an analogue of deoxynybomycin (6DNM), an antibiotic active only against Grampositive pathogens,i ndeed enabled the functionalized derivative 6DNM-NH 3 to act against av ariety of Gram-negative bacteria ( Figure 4). [59,60] In the meantime,t he limitations of current compound libraries have been understood and contemporary approaches are being pursued to broaden the chemical space used for antibacterial screenings.N ew libraries are generated using combinatorial and diversity-oriented synthesis [61][62][63][64] or smallmolecule fragments. [65][66][67][68] These libraries are mostly used for the targeted screening of purified proteins.…”

Chemical probes and drug leads from advances in synthetic planning and methodology

“…6). 174–185 The following four vignettes provide more detailed examples of the value of this approach in generating compounds that can be used to study and possibly treat infectious diseases.…”

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

“…Die retrospektive Analyse verschiedener Screening-Vorhaben [51,[53][54][55] und jüngste Ansätze,d ie bakterielle Zellpenetration experimentell zu verfolgen und zu optimieren, haben bislang zu eher vagen und manchmal auch gegensätzlichen Leitlinien geführt. Neue Substanzbibliotheken werden mithilfe von kombinatorischen oder diversitätsorientierten Synthesen [61][62][63][64] aufgebaut, oder es werden niedermolekulare Fragmente verwendet. Informatische Analysen zeigten, dass niedermolekulare Verbindungen am ehesten innerhalb der Zellen akkumulieren, wenn sie eine ionisierbare Amino-Gruppe tragen (primäre Amine sind bevorzugt), amphiphil und starr sind und darüber hinaus eine geringe Globularität aufweisen.…”

“…[59,60] In der Zwischenzeit sind die Limitierungen heutiger Substanzbibliotheken gut verstanden, und zeitgemäße Ansätze zielen darauf,den chemischen Raum fürantibakterielle Screenings zu vergrçßern. Neue Substanzbibliotheken werden mithilfe von kombinatorischen oder diversitätsorientierten Synthesen [61][62][63][64] aufgebaut, oder es werden niedermolekulare Fragmente verwendet. [65][66][67][68] Diese neuen Bibliotheken werden meist fürZ ielstruktur-basierte Screenings an rekombinanten Proteinen genutzt.…”