Abstract
ABSTRACT Introduction Clostridioides difficile infection (CDI) remains a worldwide clinical problem. Increased incidence of primary infection, occurrence of hypertoxigenic ribotypes, and more frequent occurrence of drug resistant, recurrent, and non-hospital CDI, emphasizes the urgent unmet need of discovering new therapeutic targets. Areas covered We searched PubMed and Web of Science databases for articles identifying novel therapeutic targets or treatments for C. difficile from 2001 to 2021. We present an updated review on current preclinical efforts on designing inhibitory compounds against these drug targets and indicate how these could become the focus of future therapeutic approaches. We also evaluate the increasing exploitability of gut microbial-derived metabolites and host-derived therapeutics targeting VEGF-A, immune targets and pathways, ion transporters, and microRNAs as anti-C. difficile therapeutics, which have yet to reach clinical trials. Our review also highlights the therapeutic potential of re-purposing currently available agents . We conclude by considering translational hurdles and possible strategies to mitigate these problems. Expert opinion Considerable progress has been made in the development of new anti-CDI drug candidates. Nevertheless, a greater comprehension of CDI pathogenesis and host-microbe interactions is beginning to uncover potential novel therapeutic targets, which can be exploited to plug gaps in the CDI drug discovery pipeline.
Highlights
Clostridioides difficile infection (CDI) remains a worldwide clinical problem
Substrates of this pathway are bound to acyl carrier proteins (ACPs) such as FabD, FabF and FabG, and undergo a series of reactions to extend their acyl chains; each elongation cycle is culminated by reduction, which is catalyzed by an enoyl-acyl carrier protein reductase
Patients with recurrent CDI (rCDI) exhibited a significant loss in colonic Slc26a3 protein, indicat ing that the downregulation of down-regulated in adenoma (DRA) by C. difficile toxins is likely occurring at the post-transcriptional level
Summary
Clostridioides difficile is a gram positive, strictly anaerobic, spore-forming bacterium capable of colonizing the gastroin testinal tract, and a leading worldwide cause of antibioticassociated and healthcare-acquired infectious diarrhea [1]. Adhesion and motility-associated factors, such as surface layer protein (SlpA), cell wall protein 84 (Cwp84), flagellar components, and the presence of C. difficile binary toxin CDT, all play roles in CDI pathogenesis [9,10] Certain ribotypes, such as 027 and 078, are associated with severe infection [11,12,13], deter minants of disease severity and recurrence risk are largely shaped by the complex host immune response to CDI, much of which remains poorly understood. We highlight new potential therapeutic tar gets for CDI treatment, examining different strategies These range from repurposed drugs aimed at C. difficile to new precision therapeutics that target C. difficile virulence factors, as well as and precision immune- and epigenetic therapeutic approaches that modulate the host immune and inflammatory response (Figure 1). We describe the perceived challenges in bringing these new approaches to the clinic
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