Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile

Cao, Xinyun; Boyaci, Hande; Chen, James; Bao, Yu; Landick, Robert; Campbell, Elizabeth A.

doi:10.1038/s41586-022-04545-z

Cited by 31 publications

(36 citation statements)

References 58 publications

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“…Like rpoZ in the super majority of bacteria, ctl0286 is located immediately downstream of gmk (Table 2 and data not shown). AlphaFold-predicted threedimensional structures of CTL0286 exhibit strong similarities to experimental three-dimensional structures of ω subunits for a broad range of bacterial taxa (29,101,109,113,114). AlphaFold-Multimer predicted three-dimensional structures of complexes of CTL0286, with C. trachomatis RNAP β' subunit, and of CTL0286 with C. trachomatis RNAP β' and β subunits, exhibit strong similarity to experimental three-dimensional structures of ω-β' and β'-β complexes [(Fig.…”

Section: Discussionmentioning

confidence: 74%

Identification and structural modeling of the chlamydial RNA polymerase omega subunit

Cheng

Ghatak

et al. 2022

Preprint

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Gene transcription in bacteria is carried out by the multisubunit RNA polymerase (RNAP), which is composed of a catalytic core enzyme and a promoter-recognizing σ factor. RNAP core enzyme comprises two α subunits, one β subunit, one β’ s subunit, and one ω (omega) subunit. Across multiple bacterial taxa, the RNAP ω subunit plays critical roles in the assembly of RNAP core enzyme and in other cellular functions, including regulation of bacterial growth, stress response, and biofilm formation. However, for several intracellular bacterium, including the obligate intracellular bacterium Chlamydia, no RNAP ω subunit previously has been identified. Here, we report the identification of Chlamydia trachomatis hypothetical protein CTL0286 as the chlamydial RNAP ω ortholog, based on sequence, synteny, and AlphaFold and AlphaFold-Multimer three-dimensional-structure predictions. We conclude that CTL0286 functions as the previously missing chlamydial ω ortholog. Extensions of our analysis indicate that all obligate intracellular bacteria have ω orthologs.IMPORTANCEChlamydiae are common mammalian pathogens. Chlamydiae have a unique developmental cycle characterized with an infectious but nondividing elementary body (EB), which can temporarily survive outside host cells, and a noninfectious reticulate body (RB), which replicates only intracellularly. Chlamydial development inside host cells can be arrested during persistence in response to adverse environmental conditions. Transcription plays a central role in the progression of the chlamydial developmental cycle as well as entry into and recovery from persistence. The identification of the elusive ω subunit of chlamydial RNAP makes possible future study of its regulatory roles in gene expression during chlamydial growth, development, and stress responses. This discovery also paves the way to prepare and study the intact chlamydial RNAP and its interactions with inhibitors in vitro.

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Section: Discussionmentioning

confidence: 74%

Identification and structural modeling of the chlamydial RNA polymerase omega subunit

Cheng

Ghatak

et al. 2022

Preprint

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“…Developing narrow spectrum antimicrobial or antivirulence approaches with little disruption to the human microbial ecosystem would be an ideal strategy for cancer control. For example, fidaxomicin selectively targets Clostridium difficile with minimal effects on gut commensals, as supported by findings that a fidaxomicin-binding determinant of RNA polymerase is present in C. difficile but is absent in intestinal bacteria 139. Another example is sequence-specific antimicrobials based on programmed CRISPR-Cas13a packaged into a bacteriophage capsid, which potentially target antimicrobial-resistant bacteria 140.…”

Section: Tumour Microenvironmentmentioning

confidence: 95%

Cancer as microenvironmental, systemic and environmental diseases: opportunity for transdisciplinary microbiomics science

Inamura

Hamada

Bullman

et al. 2022

Gut

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Cancer is generally regarded as a localised disease, with the well-established role of the tumour microenvironment. However, the realm of cancer goes beyond the tumour microenvironment, and cancer should also be regarded as a systemic and environmental disease. The exposome (ie, the totality of exposures), which encompasses diets, supplements, smoking, alcohol, other lifestyle factors, medications, etc, likely alters the microbiome (inclusive of bacteria, viruses, archaea, fungi, parasites, etc) and immune system in various body sites and influences tumour phenotypes. The systemic metabolic/inflammatory status, which is likely influenced by exposures and intestinal physiological changes, may affect tissue microenvironment of colorectum and any other organs. Germline genomic factors can modify disease phenotypes via gene-by-environment interactions. Although challenges exist, it is crucial to advance not only basic experimental research that can analyse the effects of exposures, microorganisms and microenvironmental components on tumour evolution but also interdisciplinary human population research that can dissect the complex pathogenic roles of the exposome, microbiome and immunome. Metagenomic, metatranscriptomic and metabolomic analyses should be integrated into well-designed population research combined with advanced methodologies of artificial intelligence and molecular pathological epidemiology. Ideally, a prospective cohort study design that enables biospecimen (such as stool) collection before disease detection should be considered to address reverse causation and recall biases. Robust experimental and observational research together can provide insights into dynamic interactions between environmental exposures, microbiota, tumour and immunity during carcinogenesis processes, thereby helping us develop precision prevention and therapeutic strategies to ultimately reduce the cancer burden.

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“…In addition, fidaxomicin has negligible activity against other bacteria constituting the gut microbiota [ 15 , 16 ]. This selective activity relies on the fact that the C. difficile RNA polymerase (inhibited by fidaxomicin [ 17 ]) has a specific residue (lysine 84) that is bound by fidaxomicin and acts as a crucial sensitizer allowing fidaxomicin killing activity [ 18 ]. This specific residue is absent in gut bacteria belonging to the phyla Bacteroides and Proteobacteria [ 18 , 19 ].…”

Section: Characteristics Mechanism Of Action and Antimicrobial Activi...mentioning

confidence: 99%

“…This selective activity relies on the fact that the C. difficile RNA polymerase (inhibited by fidaxomicin [ 17 ]) has a specific residue (lysine 84) that is bound by fidaxomicin and acts as a crucial sensitizer allowing fidaxomicin killing activity [ 18 ]. This specific residue is absent in gut bacteria belonging to the phyla Bacteroides and Proteobacteria [ 18 , 19 ]. In line with the largely reported more favorable effect than other CDI treatments in terms of microbiota disruption [ 16 , 20 , 21 , 22 , 23 ], combined with its modest activity (although inhibitory at the achieved stool concentrations) against vancomycin-resistant enterococci (VRE) [ 24 ], fidaxomicin treatment resulted in a reduced frequency of novel stool culture positivity for vancomycin-resistant enterococci (VRE) and Candida spp.…”

Section: Characteristics Mechanism Of Action and Antimicrobial Activi...mentioning

confidence: 99%

Fidaxomicin for the Treatment of Clostridioides difficile Infection in Adult Patients: An Update on Results from Randomized Controlled Trials

et al. 2022

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In recently updated international guidelines, fidaxomicin is preferentially recommended as first-line treatment over vancomycin both for the first episode of CDI and for rCDI, based on the results of different randomized controlled trials (RCTs). Although noninferiority was the rule in phase-3 RCTs with regard to the primary endpoint of clinical cure, for shaping these recommendations, particular attention was devoted to the improved global cure and reduced risk of recurrent CDI (rCDI) observed with fidaxomicin compared to vancomycin in RCTs. Overall, while the major driver of choice should remain the global benefit for the patient, consideration of available resources should be necessarily weighed in the balance, since fidaxomicin still remains more costly than vancomycin. Against this background, precisely stratifying risk groups for rCDI will represent a crucial research trajectory of future real-life studies on the treatment of first CDI episodes. In the current narrative review, we discuss the updated evidence from RCTs on the efficacy of fidaxomicin for the treatment of either the first CDI episode or rCDI, which eventually supports its positioning within current treatment algorithms and guidelines.

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Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile

Cited by 31 publications

References 58 publications

Identification and structural modeling of the chlamydial RNA polymerase omega subunit

Identification and structural modeling of the chlamydial RNA polymerase omega subunit

Cancer as microenvironmental, systemic and environmental diseases: opportunity for transdisciplinary microbiomics science

Fidaxomicin for the Treatment of Clostridioides difficile Infection in Adult Patients: An Update on Results from Randomized Controlled Trials

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