George A. Jacoby

Lahey Medical Center

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David C. Hooper

Harvard University

Karen Bush

Indiana University Bloomington

Lorraine Sutton

Vanderbilt University

Antone A. Medeiros

Brown University

Ari Robicsek

Research Network (United States)

Chi Hye Park

Harvard University

John H. Tran

Howard Hughes Medical Institute

Jacob Strahilevitz

Hadassah Medical Center

Pentti Huovinen

University of Turku

R. W. Hedges

VIB-UGent Center for Plant Systems Biology

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Harvard University

Massachusetts General Hospital

Centers for Disease Control and Prevention

Lahey Hospital and Medical Center

Case Western Reserve University

Harvard University Press

National Institutes of Health

University School

Louis Stokes Cleveland VA Medical Center

Fudan University

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Mechanisms of Resistance to Quinolones

Clinical Infectious Diseases (2005)

George A. Jacoby

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.

Topoisomerase IV

Efflux

Quinolone

10.1086/428052

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Citations (884)

Updated Functional Classification of β-Lactamases

Antimicrobial Agents and Chemotherapy (2009)

Karen Bush George A. Jacoby

Two classification schemes for beta-lactamases are currently in use. The molecular classification is based on the amino acid sequence and divides beta-lactamases into class A, C, and D enzymes which utilize serine for beta-lactam hydrolysis and class B metalloenzymes which require divalent zinc ions for substrate hydrolysis. The functional classification scheme updated herein is based on the 1995 proposal by Bush et al. (K. Bush, G. A. Jacoby, and A. A. Medeiros, Antimicrob. Agents Chemother. 39:1211-1233, 1995). It takes into account substrate and inhibitor profiles in an attempt to group the enzymes in ways that can be correlated with their phenotype in clinical isolates. Major groupings generally correlate with the more broadly based molecular classification. The updated system includes group 1 (class C) cephalosporinases; group 2 (classes A and D) broad-spectrum, inhibitor-resistant, and extended-spectrum beta-lactamases and serine carbapenemases; and group 3 metallo-beta-lactamases. Several new subgroups of each of the major groups are described, based on specific attributes of individual enzymes. A list of attributes is also suggested for the description of a new beta-lactamase, including the requisite microbiological properties, substrate and inhibitor profiles, and molecular sequence data that provide an adequate characterization for a new beta-lactam-hydrolyzing enzyme.

Classification scheme

Sequence (biology)

10.1128/aac.01009-09

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Citations (2,070)

The effect of coenzyme Q10 on tyrosine metabolism in guinea pigs

Biochemical and Biophysical Research Communications (1962)

Vincent G. Zannoni George A. Jacoby Bert N. La Du

Electron acceptor

Muconic acid

Dioxygenase

Catechol

10.1016/0006-291x(62)90178-x

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Citations (7)

Characterisation of a novel plasmid-mediated Î²-lactamase and its contribution to Î²-lactam resistance inPseudomonas aeruginosa

FEMS Microbiology Letters (1983)

I. N. Simpson S. J. Plested Miroslava J. Budin-Jones Jeanette Lees R. W. Hedges

Lactam

Beta-lactam

Pseudomonadales

10.1111/j.1574-6968.1983.tb00503.x

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Citations (33)

Ribosomal Ambiguity

Cold Spring Harbor Symposia on Quantitative Biology (1966)

Luigi Gorini George A. Jacoby Lee Breckenridge

It has been discovered (Gorini and Kataja, 1964) that a variety of Escherichia coli mutants, deficient in different metabolic functions, are able to grow in the absence of their specific growth factors provided that streptomycin (Sm) is present in the culture medium. This new class of mutants (not necessarily restricted to E. coli) was defined as "conditionally Sm dependent" (CSD). For one of them, a CSD mutant requiring arginine, it was shown (Gorini, Gundersen and Burger, 1961) that active ornithine transcarbamylase (OTC), the enzyme converting ornithine to citrulline, is found only in cells grown in the presence of Sm. Since enzyme production stops upon Sm removal and since Sm is ineffective in restoring activity in cell extracts, it was concluded that Sm acts on the transfer of genetic information from DNA to protein rather than on DNA replication or on the functioning of completed protein molecules. The principle was thus...

Ornithine Carbamoyltransferase

Ornithine transcarbamylase

10.1101/sqb.1966.031.01.084

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Citations (53)

An R Factor Defects to Our Side

New England Journal of Medicine (1972)

George A. Jacoby

IN the battle between antibiotics and gram-negative bacilli much of the enemy's strategy is dictated by twisted circles of DNA known as R factors. R factors replicate autonomously within the cell as extrachromosomal genetic elements that can be transferred to other strains on contact by conjugation. First recognized as the cause of multiple drug resistance among shigella in Japan in the 1950's,1 R factors are now known to be worldwide in distribution and account for much of the antibiotic resistance among gram-negative pathogens. Indeed, there is good reason to believe that they existed well before the discovery and use of . . .

Extrachromosomal DNA

10.1056/nejm197203162861110

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Citations (0)

The enzymatic defect in histidinemia

Biochemical and Biophysical Research Communications (1962)

Bert N. La Du R. Rodney Howell George A. Jacoby J. Edwin Seegmiller Vincent G. Zannoni

Heterologous expression

Heterologous

10.1016/0006-291x(62)90323-6

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Citations (66)

Prevalence of Plasmid-Mediated Quinolone Resistance

Antimicrobial Agents and Chemotherapy (2003)

George A. Jacoby Nancy A. Chow Ken B. Waites

ABSTRACT 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 β-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 β-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.

Quinolone

Pentapeptide repeat

Sparfloxacin

10.1128/aac.47.2.559-562.2003

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Citations (214)

The Effect of Streptomycin and Other Aminoglycoside Antibiotics on Protein Synthesis

Springer eBooks (1967)

George A. Jacoby Luigi Gorini

Streptomyces griseus

Aminocyclitol

Moiety

Disaccharide

Glycosidic bond

10.1007/978-3-642-46051-7_64

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Citations (30)

Perils of Prophylaxis

New England Journal of Medicine (1982)

George A. Jacoby

A major threat to patients with granulocytopenia and cancer is infection. Most infections develop from either endogenous or hospital-acquired organisms colonizing the alimentary tract and upper airways. Total reverse isolation with laminar air-flow rooms and microbial suppression with oral nonabsorbable antibiotics are effective in reducing infection, but their application is limited by expense and patient compliance.1 Hence, reports that oral prophylaxis with trimethoprim–sulfamethoxazole (TMP-SMX) without isolation precautions was also protective in patients with granulocytopenia have led to widespread adoption of this regimen.In this issue, Wilson and Guiney report on two patients with acute leukemia and granulocytopenia who were receiving . . .

Isolation

Regimen

Trimethoprim

10.1056/nejm198201073060111

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Citations (20)