Repurposing a platelet aggregation inhibitor ticagrelor as an antimicrobial against Clostridioides difficile

Abstract

Drug resistance in Clostridioides difficile becomes a public health concern worldwide, especially as the hypervirulent strains show decreased susceptibility to the first-line antibiotics for C. difficile treatment. Therefore, the simultaneous discovery and development of new compounds to fight this pathogen are urgently needed. in order to determinate new drugs active against C. difficile, we identified ticagrelor, utilized for the prevention of thrombotic events, as exhibiting potent growth-inhibitory activity against C. difficile. Whole-cell growth inhibition assays were performed and compared to vancomycin and metronidazole, followed by determining time-kill kinetics against C. difficile. Activities against biofilm formation and spore germination were also evaluated. Leakage analyses and electron microscopy were applied to confirm the disruption of membrane structure. Finally, ticagrelor's ability to synergize with vancomycin and metronidazole was determined using checkerboard assays. our data showed that ticagrelor exerted activity with a MIC range of 20-40 µg/mL against C. difficile. this compound also exhibited an inhibitory effect on biofilm formation and spore germination. Additionally, ticagrelor did not interact with vancomycin nor metronidazole. Our findings revealed for the first time that ticagrelor could be further developed as a new antimicrobial agent for fighting against C. difficile.A Gram-positive, spore-forming bacterium Clostridioides difficile, formerly known as Clostridium difficile is currently one of the most concerning nosocomial pathogens 1 . C. difficile tops the list of nosocomial infections with the annual estimation of more than 200,000 cases and $1 billion healthcare costs in the United States alone 2 . It has been postulated that C. difficile infection (CDI) in humans may come from animals as an overlap between human and animal isolates has been observed 3 . Patients with CDI can appear asymptomatic, however, the excessive use of antibiotics can cause an alteration in indigenous gut microbiota, enabling C. difficile to populate, produce toxins and become pathogenic, thereby causing severe diarrhoea, pseudomembranous colitis and occasionally fatality, especially in patients aged more than 65 4 . The treatment for CDI is currently limited to vancomycin, metronidazole, and fidaxomicin 5 , however, increase in treatment failures CDI due to recurrence has rendered these antibiotics ineffective 6 . Although metronidazole was initially used as the first-line agent for treatment of non-severe CDI cases and vancomycin was a drug of choice for more severe and recurrent CDI 4 , however, recent guidelines from the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) suggests that either vancomycin or fidaxomicin is recommended over metronidazole for an initial episode of CDI, unless in the setting where access to these drugs are limited 5-7 . Emergence of resistant strains to these antibiotics has been demonstrated, causing reduction in t...

Non-Antimicrobial Adjuvant Therapy Using Ticagrelor Reduced Biofilm-Related Staphylococcus aureus Prosthetic Joint Infection

“…Limitations of the study: We were not able to study the mechanism of antibacterial activity of ticagrelor. However, the leakage of cellular components has been identified as a possible mechanism for its bactericidal activity (Phanchana et al, 2020). The pathogenesis for PJI is complex and the animal model we used was chosen for its simplicity but it is not an ideal representation of human infections.…”

High-throughput profiling of drug interactions in Gram-positive bacteria

“…While non-antibiotic drugs have been proposed as anti-infective adjuvants for decades 5, 6 , the in vivo relevance and molecular basis of their antibacterial action is known only for a few examples 6, 8, 18, 51, 62, 63 . Here we further studied the antiaggregant ticagrelor, whose repurposing as an anti-infective adjuvant for Gram-positive bacteria has been recently proposed 49, 64 . While the in vivo benefit of ticagrelor for systemic infections has been documented 47, 51 , we exposed here a large number of additional synergies with antibiotics in S. aureus (n = 13), and provided molecular insights into how ticagrelor affects S. aureus physiology and potentiates the activity of positively-charged antibiotics, such as aminoglycosides or nisin.…”

Design and Synthesis of Novel Antimicrobial Agents

“…Hence, ticagrelor may function as an effective adjuvant therapy for S. aureus PJI, but additional research is required to fully understand how it works. Ticagrelor was also utilized to stop the growth of C. difficile by Phanchana et al [ 169 ] using whole-cell growth inhibition assays. Data show that ticagrelor, which has a MIC range of 20–40 μg/mL against C. difficile , inhibits the growth of biofilms and the germination of spores.…”