Research ArticleANTIMICROBIALS

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

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Science Translational Medicine  06 Sep 2017:
Vol. 9, Issue 406, eaah6813
DOI: 10.1126/scitranslmed.aah6813

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Forcing microbes to make a difficult decision

Clostridium difficile infects hundreds of thousands of people a year and is becoming increasingly difficult to treat. While investigating a C. difficile–specific antimicrobial derived from a genetically modified bacteriocin, Kirk et al. isolated strains resistant to the treatment, which were found to have mutations in the surface layer. The mutants had defensive defects and attenuated virulence but were still able to colonize the gut of hamsters. In addition to revealing biology about C. difficile, these findings showcase how making targeted antimicrobials can force bacteria into forgoing virulence in favor of survival.

Abstract

There is a medical need for antibacterial agents that do not damage the resident gut microbiota or promote the spread of antibiotic resistance. We recently described a prototypic precision bactericidal agent, Av-CD291.2, which selectively kills specific Clostridium difficile strains and prevents them from colonizing mice. We have since selected two Av-CD291.2–resistant mutants that have a surface (S)-layer–null phenotype due to distinct point mutations in the slpA gene. Using newly identified bacteriophage receptor binding proteins for targeting, we constructed a panel of Avidocin-CDs that kills diverse C. difficile isolates in an S-layer sequence-dependent manner. In addition to bacteriophage receptor recognition, characterization of the mutants also uncovered important roles for S-layer protein A (SlpA) in sporulation, resistance to innate immunity effectors, and toxin production. Surprisingly, S-layer–null mutants were found to persist in the hamster gut despite a complete attenuation of virulence. These findings suggest antimicrobials targeting virulence factors dispensable for fitness in the host force pathogens to trade virulence for viability and would have clear clinical advantages should resistance emerge. Given their exquisite specificity for the pathogen, Avidocin-CDs have substantial therapeutic potential for the treatment and prevention of C. difficile infections.

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