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J E Ambler

Publications and source records attributed to J E Ambler.

12 recordsLinked to original sources
PubMed2001

In vitro activity of gemifloxacin (SB-265805) compared to eleven other antimicrobial agents against streptococcal isolates, excluding Streptococcus pneumoniae.

The purpose of the study presented here was to determine the in vitro activity of gemifloxacin compared with that of 11 other antimicrobial agents (5 of them quinolones) against 400 isolates of beta-haemolytic and viridans group streptococci. The minimum inhibitory concentration values for gemifloxacin against 90% of the streptococci tested were as follows: Lancefield groups A, C and G, 0.06 microg/ml; Lancefield group B, Streptococcus mitis, Streptococcus mutans and Streptococcus bovis, 0.125 microg/ml; and Streptococcus milleri, 0.03 microg/ml. Resistance to penicillin, ampicillin and erythromycin was found mainly in the Streptococcus mitis isolates; tetracycline showed variable results, and no vancomycin resistance was encountered. Higher rates of ciprofloxacin resistance were identified in the Streptococcus bovis, mitis and mutans isolates. In conclusion, gemifloxacin was the most active quinolone tested followed by trovafloxacin, sparfloxacin, grepafloxacin, ciprofloxacin and levofloxacin, especially against isolates resistant to beta-lactam agents, macrolides and tetracycline.

Anti-Bacterial Agents↗
PubMed2000

Potent antipneumococcal activity of gemifloxacin is associated with dual targeting of gyrase and topoisomerase IV, an in vivo target preference for gyrase, and enhanced stabilization of cleavable complexes in vitro.

We investigated the roles of DNA gyrase and topoisomerase IV in determining the susceptibility of Streptococcus pneumoniae to gemifloxacin, a novel fluoroquinolone which is under development as an antipneumococcal drug. Gemifloxacin displayed potent activity against S. pneumoniae 7785 (MIC, 0.06 microgram/ml) compared with ciprofloxacin (MIC, 1 to 2 microgram/ml). Complementary genetic and biochemical approaches revealed the following. (i) The gemifloxacin MICs for isogenic 7785 mutants bearing either parC or gyrA quinolone resistance mutations were marginally higher than wild type at 0.12 to 0.25 microgram/ml, whereas the presence of both mutations increased the MIC to 0.5 to 1 microgram/ml. These data suggest that both gyrase and topoisomerase IV contribute significantly as gemifloxacin targets in vivo. (ii) Gemifloxacin selected first-step gyrA mutants of S. pneumoniae 7785 (gemifloxacin MICs, 0.25 microgram/ml) encoding Ser-81 to Phe or Tyr, or Glu-85 to Lys mutations. These mutants were cross resistant to sparfloxacin (which targets gyrase) but not to ciprofloxacin (which targets topoisomerase IV). Second-step mutants (gemifloxacin MICs, 1 microgram/ml) exhibited an alteration in parC resulting in changes of ParC hot spot Ser-79 to Phe or Tyr. Thus, gyrase appears to be the preferential in vivo target. (iii) Gemifloxacin was at least 10- to 20-fold more effective than ciprofloxacin in stabilizing a cleavable complex (the cytotoxic lesion) with either S. pneumoniae gyrase or topoisomerase IV enzyme in vitro. These data suggest that gemifloxacin is an enhanced affinity fluoroquinolone that acts against gyrase and topoisomerase IV in S. pneumoniae, with gyrase the preferred in vivo target. The marked potency of gemifloxacin against wild type and quinolone-resistant mutants may accrue from greater stabilization of cleavable complexes with the target enzymes.

Anti-Infective Agents↗
PubMed1999

Activity of gemifloxacin against penicillin- and ciprofloxacin-resistant Streptococcus pneumoniae displaying topoisomerase- and efflux-mediated resistance mechanisms.

Nine penicillin-resistant Streptococcus pneumoniae clinical isolates from Northern Ireland, resistant to ciprofloxacin (MICs, 2 to 64 microg/ml) through topoisomerase- and/or reserpine-sensitive efflux mechanisms, were highly susceptible to gemifloxacin (MICs, 0.03 to 0. 12 microg/ml). Two strains (requiring a ciprofloxacin MIC of 64 microg/ml) carried known quinolone resistance mutations in parC, parE, and gyrB, resulting in S79F, D435V, and E474K changes, respectively. Thus, gemifloxacin is active against clinical strains exhibiting altered topoisomerase and efflux phenotypes.

Anti-Infective Agents↗
PubMed1996

Post-UV survival of Escherichia coli strains carrying more than one UV-sensitising plasmid.

The post-UV phenotypes conferred by wild-type plasmids R391 and pYD1, which increase UV-induced mutagenesis but sensitise Escherichia coli AB1157 umuC+ uvrB+ to UV, were compared, alone and in combination with that of plasmid pGW16, which sensitises AB1157 to low, but protects against high UV doses. All three plasmids increased UV resistance when present in Shigella sonnei. No plasmid significantly affected the UV sensitivity of E. coli TK501 umuC uvrB, in which pKM101, the parent of pGW16 increases UV resistance up to 1000-fold. Both pYD1 and R391 reduced the UV protective effect of pKM101, and increased UV-sensitisation conferred by pGW16. UV-sensitisation conferred by pYD1 and R391 was additive when the plasmids were together in strain AB1157, and both pKM101 and pGW16 reduced this additive sensitisation.

DNA Repair↗
PubMed1995

Positive R plasmid mutator effect on chromosomal mutation to nalidixic acid resistance in nalidixic acid-exposed cultures of Escherichia coli.

Mutation frequencies to nalidixic acid resistance (15 mg/L in nutrient agar) were determined for derivatives of Escherichia coli AB1157 carrying the mutator plasmids R46, R391 or pYD1, or the non-mutator plasmid RP4. Frequencies of mutation remained constant in cultures of AB1157(R46) growing exponentially in drug-free broth, at a level about 12-fold higher than in the strain without plasmid. Mutation frequencies in cultures of strains AB1157(R391) and AB1157(pYD1) were about three times greater than in the control, whereas plasmid RP4 had no effect on spontaneous mutation frequency to nalidixic acid resistance. Exposure of strain AB1157 to 6 mg/L nalidixic acid in nutrient broth killed 80% of cells after 4 h. This enriched the proportion of nalidixic acid-resistant cells present in the surviving cell population giving enhanced "apparent" mutation frequencies. These were further increased by cell division of resistant mutants in the nalidixic acid-containing medium. "Apparent" resistance mutation frequencies in nalidixic acid-exposed cultures of the R46-, R391- or pYD1-carrying derivatives were, at their peak, 447-, 53- and 38-fold higher than in the control, the strain without plasmid, or the RP4-containing strain, respectively. These data illustrate how mutator plasmids like R391 and pYD1, which mediate only small increases in spontaneous mutation, can contribute to the development of clinically-significant levels of quinolone resistance.

Conjugation, Genetic↗
PubMed1993

Mutator plasmid in a nalidixic acid-resistant strain of Shigella dysenteriae type 1.

A clinical isolate of Shigella dysenteriae from Kashmir, resistant to seven antibacterial agents including nalidixic acid, carried four plasmids, only one of which was transferable by conjugation. This plasmid, designated pYD1, conferred trimethoprim resistance and increased the frequency of mutation to nalidixic acid resistance in recipient strains. Thus, although nalidixic acid resistance was not carried on a transferable plasmid, the presence of pYD1 increased the frequency at which the strain mutated to nalidixic acid resistance.

Conjugation, Genetic↗
PubMed1972

Iron-stress Response in Mixed and Monocultures of Soybean Cultivars.

Hawkeye (Fe-efficient) and PI-54619-5-1 (Fe-inefficient) soybeans (Glycine max [L.] Merr.) were grown in mixed and monoculture nutrient solutions to evaluate an inhibitory effect of PI-54619-5-1 on the uptake of Fe by Hawkeye. The ability of Hawkeye to take up Fe (Fe-stress response) was dependent on the degree of Fe stress (Fe deficiency) and was not the result of an inhibitory substance released by PI-54619-5-1 in mixed culture (Hawkeye + PI-54619-5-1).The degree of Fe stress in Hawkeye was dependent on the amount of Fe taken up by the plant. Hawkeye took up more Fe and developed less Fe stress in mixed than in monoculture because in mixed culture PI-54619-5-1 did not utilize Fe as efficiently as Hawkeye which allowed more Fe to be available per HA plant. Thus, Fe-stress response, rather than any inhibitory substances produced by PI-54619-5-1 plants, controls the uptake of Fe in Hawkeye soybean.

Journal Article↗
PubMed1970

Effect of zinc on translocation of iron in soybean plants.

Zinc interfered with translocation of iron from roots to above ground parts of Glycine max. (L.) Merrill var. Hawkeye. During periods in which zinc impeded iron translocation, it also suppressed the production of reductant by roots. Addition of iron, as a ferric metal chelate (iron ethylenediaminedihydroxyphenylacetic acid), to the growth medium overcame the interference of zinc. In the root epidermis, potassium ferricyanide formed a precipitate (Prussian blue) with ferrous iron derived from the previously supplied iron ethylenediaminedihydroxyphenylacetic acid. The reduction of ferric iron was suppressed by zinc.

Journal Article↗