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Jul 15, 2014

Bacteria Can Use CRISPR-Cas9 to Maintain Antibiotic Resistance

  • CRISPR-Cas9, celebrated as a gene editing tool in biotechnology, has multiple functions in bacteria. The most obvious function, of course, is the destruction of foreign nucleic acids, just the thing to fend off bacteriophages. A less obvious but nonetheless important function, it turns out, is the maintenance of membrane integrity. This function may serve to resolve envelope stress, which can occur during bacteriophage infection and transformation. It can also promote antibiotic resistance.

    This additional function of CRISPR-Cas9 in bacteria became clear when researchers compared bacteria that contained the usual gene for Cas9 with bacteria that contained a mutated version of the gene. These researchers, who represented the Emory University School of Medicine and the Emory Vaccine Center, found that when the gene was mutated, bacterial become more vulnerable to polymyxin B as well as standard antibiotic treatments such as streptomycin and kanamycin. They were able to trace the effects of the mutation back to a defect in envelope integrity.

    The researchers, led by David Weiss, Ph.D., determined that Cas9 regulates production of a lipoprotein that appears to alter membrane permeability. “The mutant bacteria are more permeable to certain chemicals from the outside,” said Dr. Weiss. “That increased permeability also seems to make them more likely to set off alarms when they are infecting mammalian cells.”

    These findings were detailed July 14 in the Proceedings of the National Academy of Sciences, in a paper entitled, “A CRISPR-Cas system enhances envelope integrity mediating antibiotic resistance and inflammasome evasion.” In this paper, the importance of membrane integrity is summarized as follows: “This action ultimately provides increased resistance to numerous membrane stressors, including antibiotics. We further find that this previously unappreciated function of Cas9 is critical during infection, as it promotes evasion of the host innate immune absent in melanoma 2/apoptosis associated speck-like protein containing a CARD (AIM2/ASC) inflammasome.”

    By suppressing the escape of bits of their own DNA, bacteria effectively muffle the host’s alarm system. Thus, another function for CRISPR-Cas9 in bacteria is the promotion of virulence. Such functionality could explain an earlier finding, published in Nature in 2013, about Francisella novicida, the same model organism used in the current study.

    According to the Nature study, Cas9 appears to be necessary for F. novicida to evade the mammalian immune system. What’s more, F. novicida, which infects rodents and only rarely infects humans, probably isn’t the only pathogen that is able to use Cas9 for innate immune evasion. According to Dr. Weiss’ team, a Cas9 mutant in Campylobacter jejuni, a bacterium that is a common cause of human gastroenteritis, also has increased permeability and impaired antibiotic resistance.

    The findings add to recent discoveries where Cas9 has been found to be involved in virulence in various pathogenic bacteria such as Campylobacter and Neisseria meningitides.


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