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2016 ; 1
(3
): ? Nephropedia Template TP
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CRISPR-Cas and Restriction-Modification Act Additively against Conjugative
Antibiotic Resistance Plasmid Transfer in Enterococcus faecalis
#MMPMID27303749
Price VJ
; Huo W
; Sharifi A
; Palmer KL
mSphere
2016[May]; 1
(3
): ? PMID27303749
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Enterococcus faecalis is an opportunistic pathogen and a leading cause of
nosocomial infections. Conjugative pheromone-responsive plasmids are
narrow-host-range mobile genetic elements (MGEs) that are rapid disseminators of
antibiotic resistance in the faecalis species. Clustered regularly interspaced
short palindromic repeat (CRISPR)-Cas and restriction-modification confer
acquired and innate immunity, respectively, against MGE acquisition in bacteria.
Most multidrug-resistant E. faecalis isolates lack CRISPR-Cas and possess an
orphan locus lacking cas genes, CRISPR2, that is of unknown function. Little is
known about restriction-modification defense in E. faecalis. Here, we explore the
hypothesis that multidrug-resistant E. faecalis strains are immunocompromised. We
assessed MGE acquisition by E. faecalis T11, a strain closely related to the
multidrug-resistant hospital isolate V583 but which lacks the ~620 kb of
horizontally acquired genome content that characterizes V583. T11 possesses the
E. faecalis CRISPR3-cas locus and a predicted restriction-modification system,
neither of which occurs in V583. We demonstrate that CRISPR-Cas and
restriction-modification together confer a 4-log reduction in acquisition of the
pheromone-responsive plasmid pAM714 in biofilm matings. Additionally, we show
that the orphan CRISPR2 locus is functional for genome defense against another
pheromone-responsive plasmid, pCF10, only in the presence of cas9 derived from
the E. faecalis CRISPR1-cas locus, which most multidrug-resistant E. faecalis
isolates lack. Overall, our work demonstrated that the loss of only two loci led
to a dramatic reduction in genome defense against a clinically relevant MGE,
highlighting the critical importance of the E. faecalis accessory genome in
modulating horizontal gene transfer. Our results rationalize the development of
antimicrobial strategies that capitalize upon the immunocompromised status of
multidrug-resistant E. faecalis. IMPORTANCE Enterococcus faecalis is a bacterium
that normally inhabits the gastrointestinal tracts of humans and other animals.
Although these bacteria are members of our native gut flora, they can cause
life-threatening infections in hospitalized patients. Antibiotic resistance genes
appear to be readily shared among high-risk E. faecalis strains, and multidrug
resistance in these bacteria limits treatment options for infections. Here, we
find that CRISPR-Cas and restriction-modification systems, which function as
adaptive and innate immune systems in bacteria, significantly impact the spread
of antibiotic resistance genes in E. faecalis populations. The loss of these
systems in high-risk E. faecalis suggests that they are immunocompromised, a
tradeoff that allows them to readily acquire new genes and adapt to new
antibiotics.
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