Bacterial death comes full circle: targeting plasmid replication in drug-resistant bacteria

DeNap, Johna C. B.; Hergenrother, Paul J.

doi:10.1039/b500182j

Cited by 49 publications

(32 citation statements)

References 77 publications

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“…However, the knowledge that some plasmid types are prevalent in resistant bacterial populations could be useful to explore the possibility of identifying drugs targeting these plasmid families as a medicinal strategy for the treatment of drug-resistant bacteria. An antiplasmid approach has already been proposed, based on small molecules targeting specific replication control mechanisms, inducing plasmid elimination (28). The antiplasmid approach may one day rejuvenate those antibiotics that are no longer effective due to the prevalence of specific resistance plasmid families, enabling them to be effective once again.…”

Section: Targeting Plasmids Among Enterobacteriaceae-concluding Remarksmentioning

confidence: 99%

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Resistance Plasmid Families in Enterobacteriaceae

Carattoli

2009

Antimicrob Agents Chemother

1,106

860

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Section: Targeting Plasmids Among Enterobacteriaceae-concluding Remarksmentioning

confidence: 99%

“…These criteria are best met by traits concerned with plasmid maintenance, especially replication controls (28). In 1971, Hedges and Datta proposed a plasmid classification scheme based on the stability of plasmids during conjugation, a phenomenon called plasmid incompatibility (27,47).…”

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confidence: 99%

Resistance Plasmid Families in Enterobacteriaceae

Carattoli

2009

Antimicrob Agents Chemother

1,106

860

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“…These criteria are best met by traits concerned with plasmid maintenance, especially replication controls (DeNap and Hergenrother, 2005). In 1971 Datta and Hedges proposed a plasmid classification scheme based on the stability of plasmids during conjugation, a phenomenon called plasmid incompatibility (Datta and Hedges, 1971).…”

Section: Detection and Classification Of Plasmids Carrying Esbl And/omentioning

confidence: 99%

Scientific Opinion on the public health risks of bacterial strains producing extended-spectrum β-lactamases and/or AmpC β-lactamases in food and food-producing animals

2011

EFSA Journal

246

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The potential contribution of food-producing animals or foods to public health risks by ESBL and/or AmpCproducing bacteria is related to specific plasmid-mediated ESBL and/or AmpC genes encoded by a number of organisms. The predominant ESBL families encountered are CTX-M, TEM, and SHV; the predominant AmpCfamily is CMY. The most common genes associated with this resistance in animals are bla CTX-M-1 (the most commonly identified ESBL), and bla CTX-M-14 , followed by bla and bla Among the genes encoding AmpC-type β-lactamases, bla CMY-2 is the most common.The bacterial species most commonly identified with these genes are Escherichia coli and non-typhoidal Salmonella. ESBL/AmpC transmission is mainly driven by integrons, insertion sequences, transposons and plasmids, some of which are homologous in isolates from both food-production animals and humans. Cefotaxime is used as the drug of choice for optimum detection of bla ESBL and/or bla AmpC genes. The preferred method for isolation of ESBL-and/or AmpC-producers is screening on selective agar preceded by selective enrichment in a broth.The establishment of risk factors for occurrence of ESBL/AmpC-producing bacteria is particularly complicated by the data unavailability or lack of its accuracy. The use of antimicrobials is a risk factor for the selection and spread of resistant clones, resistance genes and plasmids. Since most ESBL-and AmpC-producing strains carry additional resistances to other commonly-used veterinary drugs, generic antimicrobial use is a risk factor for ESBL/AmpC and it is not restricted specifically to the use of cephalosporins. An additional risk factor is extensive trade of animals in EU MS. There are no data on the comparative efficiency of individual control options in reducing public health risks caused by ESBL and/or AmpC-producing bacteria related to food-producing animals. Prioritisation is complex, but it is considered that a highly effective control option would be to stop all uses of cephalosporins/systemically active 3 rd /4 th generation cephalosporins, or to restrict their use (use only allowed under specific circumstances). As co-resistance is an important issue, it is also of high priority to decrease the total antimicrobial use in animal production in the EU. KEY WORDSResistance, ESBLs, AmpC, occurrence, transmission, control options, public health microbiology. SUMMARYFollowing a request from the European Commission, the Panel on Biological Hazards (BIOHAZ) was asked to deliver a Scientific Opinion on the public health risks of bacterial strains producing extended-spectrum beta (β)-lactamases (ESBL) and/or AmpC β-lactamases (AmpC) in food and foodproducing animals. In particular, the Panel was asked: (i) to propose a definition of the ESBL-and/or AmpC-producing bacterial strains and genes relevant for public health and linked to food-producing animals or food borne transmission; (ii) to review the information on the epidemiology of acquired resistance to broad spectrum cephalosporins including the genes coding for ...

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“…For example, it has been suggested that small molecules that disrupt the TA interaction would free the toxin to kill the host (11)(12)(13). However, both the identity and prevalence of TA systems in pathogenic bacteria are unknown.…”

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confidence: 99%

Toxin–antitoxin systems are ubiquitous and plasmid-encoded in vancomycin-resistant enterococci

Moritz¹,

Hergenrother

2007

Proc. Natl. Acad. Sci. U.S.A.

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125

127

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Vancomycin-resistant enterococci (VRE) are common hospital pathogens that are resistant to most major classes of antibiotics. The incidence of VRE is increasing rapidly, to the point where over one-quarter of enterococcal infections in intensive care units are now resistant to vancomycin. The exact mechanism by which VRE maintains its plasmid-encoded resistance genes is ill-defined, and novel targets for the treatment of VRE are lacking. In an effort to identify novel protein targets for the treatment of VRE infections, we probed the plasmids obtained from 75 VRE isolates for the presence of toxin-antitoxin (TA) gene systems. Remarkably, genes for one particular TA pair, the mazEF system (originally identified on the Escherichia coli chromosome), were present on plasmids from 75/75 (100%) of the isolates. Furthermore, mazEF was on the same plasmid as vanA in the vast majority of cases (>90%). Plasmid stability tests and RT-PCR raise the possibility that this plasmidencoded mazEF is indeed functional in enterococci. Given this ubiquity of mazEF in VRE and the deleterious activity of the MazF toxin, disruption of mazEF with pharmacological agents is an attractive strategy for tailored antimicrobial therapy.antibiotics ͉ mazEF ͉ axe-txe ͉ relbE ͉ VRE E nterococci are the leading cause of surgical-site infections and the third leading cause of urinary tract and bloodstream infections (1, 2) and are implicated in bacterial endocarditis, intraabdominal infections, bacteremia, and meningitis (3). The intrinsic resistance of enterococci to cephalosporin and aminoglycoside antibiotics complicates treatment strategies. Historically, vancomycin has been effective in the management of enterococcal infections; however, after nearly 30 years of use, vancomycin-resistant enterococci (VRE) emerged in the mid-1980s. In a short time span, intensive care units in the U.S. have seen a dramatic increase in the percentage of enterococcal infections that are resistant to vancomycin, from 0. 4% in 1989 to 25% in 1999 (3). In fact, in a recent study, 60% of Enterococcus faecium clinical isolates were resistant to vancomycin (4).The genes encoding the elaborate protein systems that mediate vancomycin resistance generally reside on mobile genetic elements within the enterococci. In some cases, plasmids with the various vancomycin resistance gene clusters have been recovered from enterococci (5-8), although the prevalence of plasmid-encoded resistance in VRE has not been defined. Large plasmids often have intricate mechanisms by which they maintain themselves in the bacterial population. Some plasmids contain genes encoding postsegregational killing ''plasmid addiction'' systems (9, 10), in which the plasmid encodes a potent toxin and a labile antitoxin. Provided the plasmid is present, the antitoxin binds to and sequesters the toxin. However, if a plasmid-free daughter cell arises, the unstable antitoxin is degraded, and the toxic protein kills the bacterial cell from within.If toxin-antitoxin (TA) systems are prevalent and functional on ...

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Bacterial death comes full circle: targeting plasmid replication in drug-resistant bacteria

Cited by 49 publications

References 77 publications

Resistance Plasmid Families in Enterobacteriaceae

Resistance Plasmid Families in Enterobacteriaceae

Scientific Opinion on the public health risks of bacterial strains producing extended-spectrum β-lactamases and/or AmpC β-lactamases in food and food-producing animals

Toxin–antitoxin systems are ubiquitous and plasmid-encoded in vancomycin-resistant enterococci

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