A high-throughput small-molecule screen to identify a novel chemical inhibitor of Clostridium difficile.
Clostridium difficile, a highly drug-resistant Gram-positive, spore-forming bacterium, remains a leading cause of hospital-acquired diarrhoea and antibiotic-associated colitis. Clinically, only a handful of antibiotics are used for treating C. difficile infection (CDI), suggesting a necessity for the development of new treatment options. Here we performed a high-throughput screen of 2000 drug-like compounds for inhibition of C. difficile. From this screen, one compound, 5-nitro-1,10-phenanthroline (5-NP), showed potent bactericidal effects in vitro. In addition, this compound displayed high potency towards other Clostridium spp. as well as Mycobacterium bovis but not towards other tested Gram-positive and Gram-negative bacteria. Furthermore, we show that this inhibition may proceed through a metal chelation-dependent mechanism. More importantly, preliminary evidence suggests moderate efficacy for this compound in treating CDI in a murine infection model. These results present a possible basis for the further development of this compound as an antibiotic treatment for CDI.
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
David S
DS
Katzianer
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Takahiro
T
Yano
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Harvey
H
Rubin
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: junzhu@mail.med.upenn.edu.
Jun
J
Zhu
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016360:Clostridioides difficile / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy* / Q000382:microbiology; D057166:High-Throughput Screening Assays; D007501:Iron / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009163:Mycobacterium bovis / Q000187:drug effects / Q000254:growth & development; D010618:Phenanthrolines / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013045:Species Specificity; D014640:Vancomycin / Q000494:pharmacology
C524452:5-nitro-1,10-phenanthroline; D000900:Anti-Bacterial Agents; D010618:Phenanthrolines; D054852:Small Molecule Libraries; D014640:Vancomycin; D007501:Iron
Antibiotic discovery; Clostridium difficile; High-throughput screen; Small-molecule library