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G C Crumplin

Publications and source records attributed to G C Crumplin.

12 recordsLinked to original sources
PubMed1990

Mechanisms of resistance to the 4-quinolone antibacterial agents.

Because of the close structural relationship of the fluorinated 4-quinolones to the parent compound nalidixic acid the mechanism of resistance is often perceived to be the same. However, it is clear that whilst the mechanism of resistance to fluorinated 4-quinolones is essentially the same, strains that are selected as resistant to nalidixic acid generally retain sensitivity to the newer agents. A number of mutations in the chromosome of Escherichia coli have been identified and these are described. These mutations affect the interaction of quinolones with their presumed targets (DNA gyrases) and the transport of quinolones through the cell membrane. A small number of other mutations giving rise to low-level resistance to nalidixic acid, which affect neither gyrase nor membrane function, are also recognized. Despite the recognition of these mutations, the practical application of this information is hampered by lack of knowledge of the normal uptake mechanisms, the processes involved in selection and maintenance of resistance, the relationship of resistance to pathogenicity and the frequency of occurrence of these mutations.

4-Quinolones↗
PubMed1987

Development of resistance to ofloxacin.

As a member of the 4-quinolone group of antibacterial agents, ofloxacin shares the almost unique feature of being exempt from plasmid-borne resistance in either Gram-negative or Gram-positive bacteria. In the light of this feature, the development of resistance mediated through chromosomal mutation has been carefully studied, particularly the processes of mutation which confer resistance to levels of ofloxacin approaching those obtained at the site of infection after oral administration. With Escherichia coli strain KL16 being used as a model system, the genetics of the development of resistance to ofloxacin at least 2 mg/L have been studied. In common with many in vitro studies of the development of resistance to the newer 4-quinolones, it has been observed that the mutation frequency was extremely low (in the range 1 X 10(-10) to 1 X 10(-12) with bacteria grown under routine laboratory conditions. The resultant organisms were very slow growing, temperature sensitive and apparently auxotrophic. The mutation(s) were, however, very unstable and the mutants readily reverted to ofloxacin sensitivity in the absence of selection with ofloxacin. Subsequent studies of spontaneous mutation under growth conditions more closely related to the in vivo situation in the lumen of the gut, with limitation of oxygen supply, showed that mutation frequencies were in the order of 1 X 10(-8). Mutants obtained under these conditions displayed the same phenotype as found previously and were equally unstable. Examination of the physiology of the ofloxacin-resistant mutants has shown that they display significant metabolic defects with regard to being able to cope with environmental fluctuations.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Bacterial Agents↗
PubMed1984

Investigations into the mechanism of action of the antibacterial agent norfloxacin.

Examination of the mechanism of action of norfloxacin upon susceptible strains of Escherichia coli K12 has shown that the drug exerts a potent bactericidal effect resulting from the inhibition of the A subunit of the essential enzyme DNA gyrase. It is also shown that the use of norfloxacin can reduce the total number of bacteria at the site of an infection as well as having significant effects upon the metabolism of treated cells in the interim period between the loss of viability and cell-lysis. These effects may provide a clue to a previously unsuspected mechanism of providing symptomatic relief which functions in parallel with the elimination of viable pathogenic bacteria.

Anti-Infective Agents, Urinary↗
PubMed1981

Nitrated polycyclic aromatic hydrocarbons: potent bacterial mutagens and stimulators of DNA repair synthesis in cultured human cells.

Ten polycyclic aromatic hydrocarbons (PAHs), viz. anthracene pyrene, chrysene, perylene, fluoranthene, benzo[a]pyrene, benzo[a]pyrene, benz[a]anthracene, benzo[ghi]perylene, benzo[k]fluoranthene, have been nitrated using concentrated nitric acid and the crude nitrated mixture examined for biological activity. All the nitro PAHs examined were mutagenic to Salmonella typhimurium in the absence of a rat liver preparation. Addition of Aroclor-1254 induced liver had little effect on mutagenicity. Mutagenic potency differed for the various nitrated mixtures with nitrated pyrene and nitrated fluoranthene the most potent and nitrated anthracene the least potent. Both frame-shift and base-substitution mutations were induced by the nitrated PAHs. The nitrated PAHs were also able to induce DNA repair synthesis in cultured HeLa cells in the absence of liver, indicating that these cells have the necessary enzymes to activate nitro PAHs. Potency again varied from compound to compound with nitrated pyrene appearing to be the most active. Isolation of individual components from the crude nitrated mixtures has not been carried out in this study. In view of the possible wide-spread distribution of nitrated PAHs in the environment further work is required to assess the carcinogenic potency of these compounds which possibly pose a risk to man.

Animals↗
PubMed1975

Nalidixic acid: an antibacterial paradox.

Nalidixic acid was found to be most bactericidal against various species of gram-negative bacteria at 50 to 200 mug/ml. With all species tested, increases in the concentration of nalidixic acid above this range reduced, rather than increased, its bactericidal effect so that, at levels in the region of 400 mug/ml, the drug was relatively bacteriostatic. Therefore, the mode of action of nalidixic acid at various concentrations was investigated. It was found that at the most bactericidal concentration deoxyribonucleic acid synthesis, but no ribonucleic acid (RNA) or protein synthesis, was inhibited. However at higher concentrations, where the drug is least bactericidal, both RNA and protein synthesis were found to be inhibited. Results are presented which suggest that the protein synthesis inhibition is a secondary manifestation of the ability of the drug to inhibit RNA synthesis, and that of RNA synthesis is most likely the second target site for the action of the drug when bacteria are exposed to it in high concentrations. The clinical implications of these findings are discussed.

Bacterial Proteins↗
PubMedDate not supplied

Aspects of chemistry in the development of the 4-quinolone antibacterial agents.

The evolutionary route followed in the development of the new generations of 4-quinolone antibacterial agents, from the precursor of nalidixic acid to ciprofloxacin and ofloxacin (and beyond), is characterized by a paramount role for serendipity. All of the high-technology features such as fluorination, the presence of a piperazine ring at position 7, and the stereoisomerism of the molecule, represent only the combination of characteristics incorporated in earlier generations of nalidixic acid analogues. Although almost unprecedented levels of potency per mole have been attained along with effective broad-spectrum antibacterial activity and acceptable pharmacokinetic properties, all developments have been made and are being made in the absence of a proper knowledge of how these agents work against susceptible bacteria. The absence of this knowledge, along with our almost total ignorance of how the antibacterial activity relates to possible effects in Homo sapiens, is at present a barrier to the rational development of truly optimized 4-quinolones.

Anti-Bacterial Agents↗