Targeting Clostridioides difficile: New uses for old drugs

Chen, Jianwei; Li, Yasheng; Wang, Siqi; Zhang, Hongfang; Du, Yujie; Wu, Qiang; Wang, Hong

doi:10.1016/j.drudis.2022.03.021

Cited by 10 publications

(6 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All amines used were commercially available, except for N 1 -(quinolin-4-yl)ethane-1,2-diamine, used for the preparation of compound 32, which was synthesized as previously reported. 36 (22), or variously substituted aminoalkyl groups (31)(32)(33)(34)(35)(36)(37)(38)(39)42). Compounds 23 and 24 displayed substitution at the C2 position of the adenosine (or adenosine-like) scaffold, while 25−29 shared the [1,5-c]pyrimidin-5-amine core typical of some adenosine receptor ligands.…”

Section: Chemistrymentioning

confidence: 99%

“…21 To address the unmet critical need for CDI therapeutics, several screens of small-molecule libraries, or screens for repurposing currently approved drugs, are being carried out by several groups. 22,23 We report here our complementary approach to such studies: we aim to discover drug candidates for C. dif ficile that reduce sporulation and biofilm formation and minimize intestinal carriage by inhibiting a unique DNA adenine methyltransferase (MTase).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile-Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence

et al. 2022

View full text Add to dashboard Cite

Antivirulence agents targeting endospore-transmitted Clostridioides difficile infections are urgently needed. C. difficile-specific DNA adenine methyltransferase (CamA) is required for efficient sporulation and affects persistence in the colon. The active site of CamA is conserved and closely resembles those of hundreds of related S-adenosyl-l-methionine (SAM)-dependent methyltransferases, which makes the design of selective inhibitors more challenging. We explored the solvent-exposed edge of the SAM adenosine moiety and systematically designed 42 analogs of adenosine carrying substituents at the C6-amino group (N6) of adenosine. We compare the inhibitory properties and binding affinity of these diverse compounds and present the crystal structures of CamA in complex with 14 of them in the presence of substrate DNA. The most potent of these inhibitors, compound 39 (IC50 ∼ 0.4 μM and K D ∼ 0.2 μM), is selective for CamA against closely related bacterial and mammalian DNA and RNA adenine methyltransferases, protein lysine and arginine methyltransferases, and human adenosine receptors.

show abstract

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile-Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Here, Chen et al present a refined focus on 16 FDA-approved drugs that will be exploited for the discovery of potential anti-C. difficile drugs. 15 …”

Section: Repurposing Drugs As Anti-infective Therapiesmentioning

confidence: 99%

Drug repurposing: An effective strategy to accelerate contemporary drug discovery

Zhan

Ouyang

2022

Drug Discovery Today

View full text Add to dashboard Cite

“…Formerly a first-line treatment agent for CDI, metronidazole is now recommended for use only in patients who have limited access to vancomycin and fidaxomicin ( 3 ). Though associated with a high initial cure rate (>80%), 15–30% of patients treated with vancomycin and fidaxomicin experience a first episode of C. difficile recurrence with a subsequent increase in the risk of further CDI recurrence ( 5 ). An alternative approach to antibiotics that has been touted as the most effective method to treat refractory CDI is fecal microbiota transplantation (FMT) from healthy donors ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Antisense inhibition of RNA polymerase α subunit of Clostridioides difficile

Pal,

Seleem

2023

Microbiol Spectr

View full text Add to dashboard Cite

Clostridioides difficile, the causative agent of antibiotic-associated diarrhea and pseudomembranous colitis, has emerged as a major enteric pathogen in recent years. Antibiotic treatment perturbs the gut microbiome homeostasis, which facilitates the colonization and proliferation of the pathogen in the host intestine. Paradoxically, the clinical repertoire for C. difficile infection includes the antibiotics vancomycin and/or fidaxomicin. The current therapies do not address the perturbed gut microbiome, which supports the recurrence of infection after cessation of antibiotic therapy. Peptide nucleic acids (PNAs) are novel alternatives to traditional antimicrobial therapy capable of forming strong and stable complexes with RNA and DNA, thus permitting targeted inhibition of specific genes. Here, we report a novel PNA that can target the RNA polymerase α subunit ( rpoA ) in C. difficile . The designed anti- rpoA construct inhibited clinical isolates of C. difficile (minimum inhibitory concentration values ranged between 4 and 8 µM) and exhibited bactericidal activity. Furthermore, silencing of the rpoA gene suppressed the expression of genes that encode virulence factors [toxin A ( tcdA ), toxin B ( tcdB )] in C. difficile , and the gene that encodes the transcription factor stage 0 sporulation protein ( spoOA ). Interestingly, the efficacy of the designed PNA conjugate remained unaffected even when tested at different pH levels and against a high inoculum of the pathogen. The rpoA -TAT conjugate was very specific against C. difficile and did not inhibit members of the beneficial gut microflora. Taken altogether, our study confirms that the rpoA gene can be a promising narrow-spectrum therapeutic target to curb C. difficile infection. IMPORTANCE The widespread use of antibiotics can destroy beneficial intestinal microflora, opening the door for spores of Clostridioides difficile to run rampant in the digestive system, causing life-threatening diarrhea. Alternative approaches to target this deadly pathogen are urgently needed. We utilized targeted therapeutics called peptide nucleic acids (PNAs) to inhibit gene expression in C. difficile . Inhibition of the RNA polymerase α subunit gene ( rpo A) by PNA was found to be lethal for C. difficile and could also disarm its virulence factors. Additionally, antisense inhibition of the C. difficile rpo A gene did not impact healthy microflora. We also propose a novel approach to manipulate gene expression in C. difficile without the need for established genetic tools.

show abstract

Targeting Clostridioides difficile: New uses for old drugs

Cited by 10 publications

References 71 publications

Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile-Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence

Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile-Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence

Drug repurposing: An effective strategy to accelerate contemporary drug discovery

Antisense inhibition of RNA polymerase α subunit of Clostridioides difficile

Contact Info

Product

Resources

About