Targeting of Key Proteins In Clostridium for Modern Antibiotics
Background: Clostridium difficile is a gram-positive, spore-forming, anaerobic bacteria that is a major cause of nosocomial associated diarrhea and is difficult to treat due to its highly resistant spores. This disease primarily effects the elderly, especially those in hospital settings and often leads to dangerous levels of dehydration. Novel treatments are being developed after determining which spore proteins are associated with spore germination and dormancy resilience that should prevent recurrent infections and lower rates of mortality and antibiotic resistance. Mutation of GerS and CwlD followed by spore counting and resistance testing determined that these two spore proteins are key to spore resistance mechanisms1,2. Additionally, a hybrid antibiotic called Cadazolid is being developed, which uses a unique mechanism to bypass the resistance mechanism used in current treatments3.
Objective: This research will not only help cure C. difficile infections but also prevent initial and recurrent infections and prevent contamination of hospital environments with resistant spores.
Search Methods: An online search in the PubMed database was conducted from January of 2023 to April of 2023 using the following keywords: “Clostridium Difficile”, “Vancomycin Resistance”, and “Cadazolid mechanism of Action”.
Results: The bacteriostatic properties of Cadazolid were tested against different strains of C. difficile, including toxigenic and hypervirulent strains. The study used in vitro assays, including time-kill assays and measurement of toxin production and spore formation in order to measure efficacy of toxin neutralization rather than complete removal of C. difficile from gut microbiomes4. Cadazolid was found to be active against all strains tested, with a MIC range of 0.125 to 0.5 μg/ml and was more potent than other antibiotics such as linezolid, ciprofloxacin, and moxifloxacin. In addition to being more potent, the MICs for cadazolid were not significantly increased in linezolid-resistant strains or strains resistant to fluoroquinolones which means it can maintain lower dosing and thus have fewer side effects while being more effective5,6.
Antibiotic resistance is a growing issue that will continue to develop over time, therefore, development of novel antibiotics or treatments for bacterial infections is a critical need. Cadazolid should be further tested in clinical trials in combination with other antibiotics to demonstrate spore reduction or elimination of resurgent infections7.
Conclusion: By using narrow and specific treatment regimens, use of broad-spectrum antibiotics can be lowered, which contributes to lowering rates of mutations. Furthermore, by using antibiotics that lower resistance and persistence of spores and toxins in highly recurrent species like C. difficile, the prevalence of mutations such as those that develop into antibiotic resistance can be lowered as well8,9.
- Diaz OR, Sayer CV, Popham DL, Shen A. Clostridium difficile Lipoprotein GerS Is Required for Cortex Modification and Thus Spore Germination. mSphere. 2018;3(3):e00205-18. Published 2018 Jun 27. doi:10.1128/mSphere.00205-18
- Paredes-Sabja D, Cid-Rojas F, Pizarro-Guajardo M. Assembly of the exosporium layer in Clostridioides difficile spores. Curr Opin Microbiol. 2022;67:102137. doi:10.1016/j.mib.2022.01.008
- Scaiola A, Leibundgut M, Boehringer D, et al. Structural basis of translation inhibition by cadazolid, a novel quinoxolidinone antibiotic. Sci Rep. 2019;9(1):5634. Published 2019 Apr 4. doi:10.1038/s41598-019-42155-4
- Locher HH, Seiler P, Chen X, et al. In vitro and in vivo antibacterial evaluation of cadazolid, a new antibiotic for treatment of Clostridium difficile infections. Antimicrob Agents Chemother. 2014;58(2):892-900. doi:10.1128/AAC.01830-13
- Feuerstadt P, Louie TJ, Lashner B, et al. SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection. N Engl J Med. 2022;386(3):220-229. doi:10.1056/NEJMoa2106516
- Mühlberg E, Umstätter F, Kleist C, Domhan C, Mier W, Uhl P. Renaissance of vancomycin: approaches for breaking antibiotic resistance in multidrug-resistant bacteria. Can J Microbiol. 2020;66(1):11-16. doi:10.1139/cjm-2019-0309
- Cadazolid for the treatment of Clostridium difficile infection: results of two double-blind, placebo-controlled, non-inferiority, randomized phase 3 trials
Gerding, Dale N et al. The Lancet Infectious Diseases, Volume 19, Issue 3, 265 – 274
- Shen, Aimee. (2012). Clostridium difficile Toxins: Mediators of Inflammation. Journal of innate immunity. 4. 149-58. 10.1159/000332946.