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Antimicrob Agents Chemother. 2019 Dec 20;64(1). pii: e01074-19. doi: 10.1128/AAC.01074-19. Print 2019 Dec 20.

cfr(B), cfr(C), and a New cfr-Like Gene, cfr(E), in Clostridium difficile Strains Recovered across Latin America.

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Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA.
CIET and Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
Escuela de Microbiología, Facultad de Ciencias, Universidad Nacional Autónoma de Honduras, Tegucigalpa, Honduras.
Medical Bacteriology, Department of Microbiology, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional (ENCB-IPN), Mexico City, Mexico.
Microbiota-Host Interactions and Clostridia Research Group, Facultad Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile.
Millennium Nucleus in the Biology of Intestinal Microbiota, Santiago, Chile.
Unidad de Investigación en Enfermedades Infecciosas y Parasitarias, Instituto Mexicano del Seguro Social, Mexico City, Mexico.
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA.
CIET and Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica


Cfr is a radical S-adenosyl-l-methionine (SAM) enzyme that confers cross-resistance to antibiotics targeting the 23S rRNA through hypermethylation of nucleotide A2503. Three cfr-like genes implicated in antibiotic resistance have been described, two of which, cfr(B) and cfr(C), have been sporadically detected in Clostridium difficile However, the methylase activity of Cfr(C) has not been confirmed. We found cfr(B), cfr(C), and a cfr-like gene that shows only 51 to 58% protein sequence identity to Cfr and Cfr-like enzymes in clinical C. difficile isolates recovered across nearly a decade in Mexico, Honduras, Costa Rica, and Chile. This new resistance gene was termed cfr(E). In agreement with the anticipated function of the cfr-like genes detected, all isolates exhibited high MIC values for several ribosome-targeting antibiotics. In addition, in vitro assays confirmed that Cfr(C) and Cfr(E) methylate Escherichia coli and, to a lesser extent, C. difficile 23S rRNA fragments at the expected positions. The analyzed isolates do not have mutations in 23S rRNA genes or genes encoding the ribosomal proteins L3 and L4 and lack poxtA, optrA, and pleuromutilin resistance genes. Moreover, these cfr-like genes were found in Tn6218-like transposons or integrative and conjugative elements (ICE) that could facilitate their transfer. These results indicate selection of potentially mobile cfr-like genes in C. difficile from Latin America and provide the first assessment of the methylation activity of Cfr(C) and Cfr(E), which belong to a cluster of Cfr-like proteins that does not include the functionally characterized enzymes Cfr, Cfr(B), and Cfr(D).


23S rRNA methylation; C. difficile ; Cfr; Cfr(B); Cfr(C); Cfr(E); PhLOPSA resistance; cfr-like genes


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