New class of precision antimicrobials redefines role of Clostridium difficile S-layer in virulence and viability.

Kirk JA , Gebhart D , Buckley AM , Lok S , Scholl D , Douce GR , Govoni GR , Fagan RP

Sci Transl Med. 2017 Sep 6;9(406).

Speaker: Po-Jung Chiu(邱柏蓉)                               Time: 14:00~15:00, Dec. 13, 2007

Commentator: Dr. Yuan-Pin Hung(洪元斌醫師)     Place: Room 601

Abstract:

Increasing rates of antibiotic resistant bacteria is a pressing healthcare problem and requires the development of novel antibacterial agents. In this report, the authors focused on one particular pathogen, Clostridium difficile, one of the leading cause of nosocomial infections worldwide. Avidocin-CDs are genetically modified proteins based on R-type bacteriocins produced by C. difficile to kill competing C. difficile strains. ^[1]. These type of bacteriocins resembles a bacteriophage in structure binds to the cell wall via a receptor binding protein domain. A previous study showed that one of the Avidocin-CDs, Av-CD291.2, can block C. difficile colonization in a mouse model and has little effect on the resident gut microbiota. ^[1] In this study, the authors attempted to further characterize the mechanism of Av-CD291.2 using resistant mutants. The authors determined that Av-CD291.2 directly binds to S-layer proteins found on the cell wall of all C. difficile. S-layer proteins are made from the product of the slpA gene found and at least 13 variants (S-layer cassette types) have been identified in C. difficile. ^[2] The authors next determined that the sensitivity to Av-CD291.2 is slpA allele-specific as it is the site in which the receptor binding protein of Av-CD291.2 interact with. In addition, the authors determined that Avidocin-CD killing of C. difficile does not result in toxin release which would have undesirable effect. Interestingly, during the study, the authors observed that S-layer null mutants are sensitive to innate immune effectors, display severe sporulation defects, and are completely avirulent in hamster model of infection. In short, the authors demonstrated that Avidocin-CD have substantial therapeutic potential for the treatment and prevention of C. difficile infections.

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