London, United Kingdom
MISCELLANEOUS APPLICATIONS IN DRUG DEVELOPMENT
There have been limited reports of using an electrical detection method during the development of drugs other than those selected or designed specifically for antimicrobial activity. Dale and Edwards (1989a) used the technology to determine the relative toxicities of compounds believed to be useful bioreductive cytotoxic and radiosensitizing agents. Such agents are designed to have selective toxicicity under anaerobic conditions, to act against cells in mammalian tumors that are resistant to radiation treatment, surviving in areas of low oxygen tension. E. coli was selected as a microbial model and was grown under aerobic and anaerobic conditions in broths containing increasing concentrations of the drugs. Growth of the bacteria was monitored via conductance measurements, enabling a D50 value (the drug concentration that had a detection time twice
that of an untreated suspension) for each drug under aerobic and anaerobic conditions to be calculated. A comparison of the relative toxicity under the two growing conditions could then be made. Because this in vitro study showed results similar to those of previous in vivo studies, Dale and Edwards (1989a) suggested that electrical detection was useful for rapid screening of these cytotoxic agents.
Examining the conductance curves of wild type and mutant strains of E. coli in the presence and absence of drugs has led to the elucidation of the mode of action of a cytotoxic drug (Dale and Edwards 1989b) and the development of a screen for mutagenic agents (Forsythe 1990). Alteration in the growth parameters of three mutants with known defects in specific DNA repair in the presence of a drug, compared to a wild type strain, gave an indication of how the function of DNA was impaired by the drug (Dale and Edwards 1989b). Using a similar procedure with a wild type E. coli strain and a single DNA-repair mutant, Forsythe (1990) was able to classify a range of drugs as either direct-acting mutagens or bactericidal agents. Changes in the viability of the bacterial suspensions in the presence of the drug were determined via impedance. Direct-acting mutagens were indicated when there was a loss of viability in the mutant population but no change in the viability of the wild type suspension, whereas an equal loss of viability in both cell populations indicated bactericidal activity only.
A further application of impedance was reported by Frenoy et al. (1994). They studied the in vivo phagocytosis of a bacterial population infused into an animal model by determining the electrical detection times of blood samples. Using a correlation established between detection times and cell numbers, they calculated the rate of clearance of bacteria from the bloodstream. The technique was used in evaluating the reticuloendothelial system-stimulating properties of a drug administered to the test animals, and it was shown to give results similar to those of the standard in vivo method of carbon clearance.
CONCLUSION
This review has illustrated the large number of potential applications that impedance microbiology has in the pharmaceutical industry. This discipline may be particularly useful in the detection of specific microorganisms in raw ingredients or final products, and it could also be applied to the qualitative analysis of biocidal agents. We emphasize that the technique, whether used in a qualitative or quantitative role, must be thoroughly validated. The literature has, however, provided reasonable detail, so that such validation can be successfully carried out, enabling realization of the full benefits of this highly automated, rapid technology.
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