Development of CRISPR-Cas13a-based antimicrobials capable of sequence-specific killing of target bacteria

Kotaro Kiga, Xin-Ee Tan, Rodrigo Ibarra-Chávez, Shinya Watanabe, Yoshifumi Aiba, Yusuke Sato’o, Feng-Yu Li, Teppei Sasahara, Bintao Cui, Moriyuki Kawauchi, Tanit Boonsiri, Kanate Thitiananpakorn, Yusuke Taki, Aa Haeruman Azam, Masato Suzuki, José R. Penadés and Longzhu Cui ()
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Kotaro Kiga: Division of Bacteriology, Department of Infection and Immunity, School of Medicine, Jichi Medical University
Xin-Ee Tan: Division of Bacteriology, Department of Infection and Immunity, School of Medicine, Jichi Medical University
Rodrigo Ibarra-Chávez: Institute of Infection, Immunity & Inflammation, University of Glasgow
Shinya Watanabe: Division of Bacteriology, Department of Infection and Immunity, School of Medicine, Jichi Medical University
Yoshifumi Aiba: Division of Bacteriology, Department of Infection and Immunity, School of Medicine, Jichi Medical University
Yusuke Sato’o: Division of Bacteriology, Department of Infection and Immunity, School of Medicine, Jichi Medical University
Feng-Yu Li: Division of Bacteriology, Department of Infection and Immunity, School of Medicine, Jichi Medical University
Teppei Sasahara: Division of Bacteriology, Department of Infection and Immunity, School of Medicine, Jichi Medical University
Bintao Cui: Division of Bacteriology, Department of Infection and Immunity, School of Medicine, Jichi Medical University
Moriyuki Kawauchi: Division of Bacteriology, Department of Infection and Immunity, School of Medicine, Jichi Medical University
Tanit Boonsiri: Division of Bacteriology, Department of Infection and Immunity, School of Medicine, Jichi Medical University
Kanate Thitiananpakorn: Division of Bacteriology, Department of Infection and Immunity, School of Medicine, Jichi Medical University
Yusuke Taki: Division of Bacteriology, Department of Infection and Immunity, School of Medicine, Jichi Medical University
Aa Haeruman Azam: Division of Bacteriology, Department of Infection and Immunity, School of Medicine, Jichi Medical University
Masato Suzuki: Antimicrobial Resistance Research Center, National Institute of Infectious Diseases
José R. Penadés: Institute of Infection, Immunity & Inflammation, University of Glasgow
Longzhu Cui: Division of Bacteriology, Department of Infection and Immunity, School of Medicine, Jichi Medical University

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract The emergence of antimicrobial-resistant bacteria is an increasingly serious threat to global health, necessitating the development of innovative antimicrobials. Here we report the development of a series of CRISPR-Cas13a-based antibacterial nucleocapsids, termed CapsidCas13a(s), capable of sequence-specific killing of carbapenem-resistant Escherichia coli and methicillin-resistant Staphylococcus aureus by recognizing corresponding antimicrobial resistance genes. CapsidCas13a constructs are generated by packaging programmed CRISPR-Cas13a into a bacteriophage capsid to target antimicrobial resistance genes. Contrary to Cas9-based antimicrobials that lack bacterial killing capacity when the target genes are located on a plasmid, the CapsidCas13a(s) exhibit strong bacterial killing activities upon recognizing target genes regardless of their location. Moreover, we also demonstrate that the CapsidCas13a(s) can be applied to detect bacterial genes through gene-specific depletion of bacteria without employing nucleic acid manipulation and optical visualization devices. Our data underscore the potential of CapsidCas13a(s) as both therapeutic agents against antimicrobial-resistant bacteria and nonchemical agents for detection of bacterial genes.

Date: 2020
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DOI: 10.1038/s41467-020-16731-6

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