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Biomedical subjects

George A Jacoby

Publications and source records attributed to George A Jacoby.

At least 19 recordsLinked to original sources
PubMed2006

Prevalence in the United States of aac(6')-Ib-cr encoding a ciprofloxacin-modifying enzyme.

Among 313 Enterobacteriaceae from the United States with a ciprofloxacin MIC of >/=0.25 microg/ml and reduced susceptibility to ceftazidime, aac(6')-Ib was present in 50.5% of isolates, and of these, 28% carried the cr variant responsible for low-level ciprofloxacin resistance. aac(6')-Ib-cr was geographically widespread, stable over time, most common in Escherichia coli, equally prevalent in ciprofloxacin-susceptible and -resistant strains, and not associated with qnr genes.

Acetyltransferases↗
PubMed2006

The worldwide emergence of plasmid-mediated quinolone resistance.

Fluoroquinolone resistance is emerging in gram-negative pathogens worldwide. The traditional understanding that quinolone resistance is acquired only through mutation and transmitted only vertically does not entirely account for the relative ease with which resistance develops in exquisitely susceptible organisms, or for the very strong association between resistance to quinolones and to other agents. The recent discovery of plasmid-mediated horizontally transferable genes encoding quinolone resistance might shed light on these phenomena. The Qnr proteins, capable of protecting DNA gyrase from quinolones, have homologues in water-dwelling bacteria, and seem to have been in circulation for some time, having achieved global distribution in a variety of plasmid environments and bacterial genera. AAC(6')-Ib-cr, a variant aminoglycoside acetyltransferase capable of modifying ciprofloxacin and reducing its activity, seems to have emerged more recently, but might be even more prevalent than the Qnr proteins. Both mechanisms provide low-level quinolone resistance that facilitates the emergence of higher-level resistance in the presence of quinolones at therapeutic levels. Much remains to be understood about these genes, but their insidious promotion of substantial resistance, their horizontal spread, and their co-selection with other resistance elements indicate that a more cautious approach to quinolone use and a reconsideration of clinical breakpoints are needed.

Anti-Bacterial Agents↗
PubMed2006

qnrB, another plasmid-mediated gene for quinolone resistance.

A novel plasmid-mediated quinolone resistance gene, qnrB, has been discovered in a plasmid encoding the CTX-M-15 beta-lactamase from a Klebsiella pneumoniae strain isolated in South India. It has less than 40% amino acid identity with the original qnr (now qnrA) gene or with the recently described qnrS but, like them, codes for a protein belonging to the pentapeptide repeat family. Strains with qnrB demonstrated low-level resistance to all quinolones tested. The gene has been cloned in an expression vector attaching a polyhistidine tag, which facilitated purification to >or=95% homogeneity. As little as 5 pM of QnrB-His6 protected purified DNA gyrase against inhibition by 2 microg/ml (6 microM) ciprofloxacin. With a PCR assay qnrB has been detected in Citrobacter koseri, Enterobacter cloacae, and Escherichia coli isolates from the United States, linked to SHV-12 beta-lactamase and coding for a product differing in five amino acids from the Indian (now QnrB1) variety. The qnrB gene has been found near Orf1005 in some, but not all, plasmids and in association with open reading frames matching known chromosomal genes, suggesting that it too was acquired by plasmids from an as-yet-unknown bacterial source.

Amino Acid Sequence↗
PubMed2006

Identification of extended-spectrum, AmpC, and carbapenem- hydrolyzing beta-lactamases in Escherichia coli and Klebsiella pneumoniae by disk tests.

Antibiotic disks with and without clavulanic acid, 3-aminophenylboronic acid, or EDTA were tested with a set of 55 Klebsiella pneumoniae and Escherichia coli strains producing well-characterized extended-spectrum, AmpC, or carbapenem-hydrolyzing beta-lactamases. A relatively simple scheme was devised for distinguishing beta-lactamase types in clinical isolates with or without intact outer membrane porins.

Anti-Bacterial Agents↗
PubMed2005

Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase.

Antimicrobial-modifying resistance enzymes have traditionally been class specific, having coevolved with the antibiotics they inactivate. Fluoroquinolones, antimicrobial agents used extensively in medicine and agriculture, are synthetic and have been considered safe from naturally occurring antimicrobial-modifying enzymes. We describe reduced susceptibility to ciprofloxacin in clinical bacterial isolates conferred by a variant of the gene encoding aminoglycoside acetyltransferase AAC(6')-Ib. This enzyme reduces the activity of ciprofloxacin by N-acetylation at the amino nitrogen on its piperazinyl substituent. Although approximately 30 variants of this gene have been reported since 1986, the two base-pair changes responsible for the ciprofloxacin modification phenotype are unique to this variant, first reported in 2003 and now widely disseminated. An intense increase in the medical use of ciprofloxacin seems to have been accompanied by a notable development: a single-function resistance enzyme has crossed class boundaries, and is now capable of enzymatically undermining two unrelated antimicrobial agents, one of them fully synthetic.

Acetylation↗
PubMed2005

Mechanisms of resistance to quinolones.

The increased use of fluoroquinolones has led to increasing resistance to these antimicrobials, with rates of resistance that vary by both organism and geographic region. Resistance to fluoroquinolones typically arises as a result of alterations in the target enzymes (DNA gyrase and topoisomerase IV) and of changes in drug entry and efflux. Mutations are selected first in the more susceptible target: DNA gyrase, in gram-negative bacteria, or topoisomerase IV, in gram-positive bacteria. Additional mutations in the next most susceptible target, as well as in genes controlling drug accumulation, augment resistance further, so that the most-resistant isolates have mutations in several genes. Resistance to quinolones can also be mediated by plasmids that produce the Qnr protein, which protects the quinolone targets from inhibition. Qnr plasmids have been found in the United States, Europe, and East Asia. Although Qnr by itself produces only low-level resistance, its presence facilitates the selection of higher-level resistance mutations, thus contributing to the alarming increase in resistance to quinolones.

Ciprofloxacin↗
PubMed2005

Interaction of the plasmid-encoded quinolone resistance protein Qnr with Escherichia coli DNA gyrase.

Quinolone resistance normally arises by mutations in the chromosomal genes for type II topoisomerases and by changes in the expression of proteins that control the accumulation of quinolones inside bacteria. A novel mechanism of plasmid-mediated quinolone resistance was recently reported that involves DNA gyrase protection by a pentapeptide repeat family member called Qnr. This family includes two other members, McbG and MfpA, that are also involved in resistance to gyrase inhibitors. Purified Qnr-His(6) was shown to protect Escherichia coli DNA gyrase directly from inhibition by ciprofloxacin. Here we have provided a biochemical basis for the mechanism of quinolone resistance. We have shown that Qnr can bind to the gyrase holoenzyme and its respective subunits, GyrA and GyrB. The binding of Qnr to gyrase does not require the presence of the complex of enzyme, DNA, and quinolone, since binding occurred in the absence of relaxed DNA, ciprofloxacin, or ATP. We hypothesize that the formation of Qnr-gyrase complex occurs before the formation of the cleavage complex. Furthermore, there was a decrease in DNA binding by gyrase when the enzyme interacted with Qnr. Therefore, it is possible that the reaction intermediate recognized by Qnr is one early in the gyrase catalytic cycle, in which gyrase has just begun to interact with DNA. Quinolones bind later in the catalytic cycle and stabilize a ternary complex consisting of the drug, gyrase, and DNA. By lowering gyrase binding to DNA, Qnr may reduce the amount of holoenzyme-DNA targets for quinolone inhibition.

Anti-Bacterial Agents↗
PubMed2004

Emerging plasmid-mediated quinolone resistance associated with the qnr gene in Klebsiella pneumoniae clinical isolates in the United States.

Although quinolone resistance commonly results from chromosomal mutation, recent studies indicate that such resistance can also be transferred on plasmids carrying the gene responsible, qnr. One hundred ten ciprofloxacin-resistant clinical isolates of Klebsiella pneumoniae and Escherichia coli from the United States were screened for the qnr gene by PCR and Southern hybridization of plasmid DNA. Conjugation experiments were done with azide-resistant E. coli J53 as the recipient and selection with azide and sulfonamide, a resistance frequently linked to qnr. EcoRI and BamHI digests of qnr-hybridizing plasmids were subjected to electrophoresis on agarose gels and probed with qnr by Southern hybridization. qnr was detected in 8 (11.1%) of 72 K. pneumoniae strains. These eight positive strains were from six states in the United States. qnr was not found in any of the 38 E. coli strains tested. Quinolone resistance was transferred from seven of the eight probe-positive strains. Transconjugants with qnr-hybridizing plasmids had 32-fold increases in ciprofloxacin MICs relative to E. coli J53. For all eight strains, the sequence of qnr was identical to that originally reported. By size and restriction digests, four plasmids were related to the first-reported plasmid, pMG252, and three were different. Five new qnr plasmids encoded FOX-5 beta-lactamase, as did pMG252, but two others produced SHV-7 extended-spectrum beta-lactamase. Transferable plasmid-mediated quinolone resistance associated with qnr is now widely distributed in quinolone-resistant clinical strains of K. pneumoniae in the United States. Plasmid-determined quinolone resistance contributes to the increasing quinolone resistance of K. pneumoniae isolates and to the linkage previously observed between resistance to quinolones and the latest beta-lactam antibiotics.

Anti-Infective Agents↗
PubMed2004

Activities of newer quinolones against Escherichia coli and Klebsiella pneumoniae containing the plasmid-mediated quinolone resistance determinant qnr.

Seventeen qnr-containing transconjugants were constructed with azide-resistant Escherichia coli J53 as the recipient, and the MICs of 12 quinolones were tested by agar dilution methods. Sitafloxacin, BAYy3118, and premafloxacin had higher activity in vitro than ciprofloxacin against transconjugants and donors containing qnr. The donors had higher quinolone MICs than the transconjugants.

Anti-Infective Agents↗
PubMed2004

Role of beta-lactamases and porins in resistance to ertapenem and other beta-lactams in Klebsiella pneumoniae.

High-level resistance to ertapenem was produced by beta-lactamases of groups 1, 2f, and 3 in a strain of Klebsiella pneumoniae deficient in Omp35 and Omp36. From a wild-type strain producing ACT-1 beta-lactamase, ertapenem-resistant mutants for which the ertapenem MICs were up to 128 microg/ml and expression of outer membrane proteins was diminished could be selected.

Anti-Bacterial Agents↗
PubMed2003

Prevalence of plasmid-mediated quinolone resistance.

Quinolone resistance encoded by the qnr gene and mediated by plasmid pMG252 was discovered in a clinical strain of Klebsiella pneumoniae that was isolated in 1994 at the University of Alabama at Birmingham Medical Center. The gene codes for a protein that protects DNA gyrase from quinolone inhibition and that belongs to the pentapeptide repeat family of proteins. The prevalence of the gene has been investigated by using PCR with qnr-specific primers with a sample of more than 350 gram-negative strains that originated in 18 countries and 24 states in the United States and that included many strains with plasmid-mediated AmpC or extended spectrum beta-lactamase enzymes. qnr was found in isolates from the University of Alabama at Birmingham only during 6 months in 1994, despite the persistence of the gene for FOX-5 beta-lactamase, which is linked to qnr on pMG252. Isolates from other locations were negative for qnr. The prevalence of mcbG in the same sample was also examined. mcbG encodes another member of the pentapeptide repeat family and is involved in immunity to microcin B17, which, like quinolones, targets DNA gyrase. A single clinical isolate contained mcbG on a transmissible R plasmid. This plasmid and one carrying the complete microcin B17 operon slightly decreased sparfloxacin susceptibility but had a much less protective effect than pMG252. Plasmid-mediated quinolone resistance was thus rare in the sample examined.

Anti-Infective Agents↗
PubMed2003

Plasmid-mediated quinolone resistance in clinical isolates of Escherichia coli from Shanghai, China.

Although quinolone resistance usually results from chromosomal mutations, recent studies indicate that quinolone resistance can also be plasmid mediated. The gene responsible, qnr, is distinct from the known quinolone resistance genes and in previous studies seemed to be restricted to Klebsiella pneumoniae and Escherichia coli isolates from the University of Alabama in Birmingham, where this resistance was discovered. In Shanghai, the frequency of ciprofloxacin resistance in E. coli has exceeded 50% since 1993. Seventy-eight unique ciprofloxacin-resistant clinical isolates of E. coli from Shanghai hospitals were screened for the qnr gene by colony blotting and Southern hybridization of plasmid DNA. Conjugation experiments were done with azide-resistant E. coli J53 as a recipient with selection for plasmid-encoded antimicrobial resistance (chloramphenicol, gentamicin, or tetracycline) and azide counterselection. qnr genes were sequenced, and the structure of the plasmid DNA adjacent to qnr was analyzed by primer walking with a sequential series of outward-facing sequencing primers with plasmid DNA templates purified from transconjugants. Six (7.7%) of 78 strains gave a reproducible hybridization signal with a qnr gene probe on colony blots and yielded strong signals on plasmid DNA preparations. Quinolone resistance was transferred from all six probe-positive strains. Transconjugants had 16- to 250-fold increases in the MICs of ciprofloxacin relative to that of the recipient. All six strains contained qnr with a nucleotide sequence identical to that originally reported, except for a single nucleotide change (CTA-->CTG at position 537) encoding the same amino acid. qnr was located in complex In4 family class 1 integrons. Two completely sequenced integrons were designated In36 and In37. Transferable plasmid-mediated quinolone resistance associated with qnr is thus prevalent in quinolone-resistant clinical strains of E. coli from Shanghai and may contribute to the rapid increase in bacterial resistance to quinolones in China.

4-Quinolones↗
PubMed2002

Regional occurrence of plasmid-mediated SHV-7, an extended-spectrum beta-lactamase, in Enterobacter cloacae in Philadelphia Teaching Hospitals.

Although the production of extended-spectrum beta-lactamases (ESBLs) by Klebsiella pneumoniae and Escherichia coli is an emerging problem, limited data are available regarding the frequency of ESBL production in other organisms. We provide the only description of regional occurrence of SHV-7 in Enterobacteriaceae other than E. coli or K. pneumoniae in the United States, and we emphasize that, among Enterobacter cloacae strains, not all resistance to extended-spectrum cephalosporins is the result of hyperproduction of AmpC beta-lactamase.

Bacterial Proteins↗