Sharpe, Catherine Ann; (1998) Antimicrobial activities of nitrofurantoin and some novel nitrofuran compounds. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The mechanism of action of nitrofurantoin against the Escherichia coli K12 strain AB1157 was investigated. Like quinolone antibacterials, nitrofurans damage DNA and induce SOS error-prone DNA repair. However, unlike the quinolones, which exhibit three separate mechanisms of action depending on whether RNA or protein synthesis or cell division is functioning, the activity of nitrofurantoin was shown not to be dependent on protein or RNA synthesis or on cell division. The resistance of Escherichia coli ABM 57, which is wild-type with respect to DNA repair, and some DNA repair-deficient mutants to nitrofurantoin decreased in the order TK702 umuC > wild-type AB1157 > AB2494 lexA > AB2470 recB > AB2463 recA > JG138 polA > TK501 uvrB umuC > JC3890 uvrB > AB1886 uvrA. Plasmid R46, which confers mutagenic error-prone DNA repair on its host, increased the minimum inhibitory concentration (MIC) of nitrofurantoin against uvrB- deficient strains but did not affect the MICs of the wild-type or other DNA repair-deficient strains. R46 conferred some protection against bactericidal concentrations of nitrofurantoin to AB1157 and the umuC, uvrA, uvrB and uvrB umuC mutants but not to the lexA, recA, recB or polA-deficient strains. Other mutator plasmids pGW12, pGW16, pKM101, pYD1, R16, R124, R144, R391, R446b, R621a and R805a, from a variety of incompatibility groups, were also tested. None affected the MIC of nitrofurantoin against E. coli strain AB1157. However, pKM101, R446b, R621a and R805a conferred some protection whereas pGW12, pGW16, R144 and R391 sensitized AB1157 to a bactericidal concentration of nitrofurantoin. E. coli AB1157 showed low spontaneous mutation to nitrofurantoin resistance. Mutation frequencies were not increased in cells exposed to an inhibitory concentration of nitrofurantoin. R46 was the only plasmid of a variety of incompatibility groups to be eliminated from E. coli AB1157 by nitrofurantoin. Nine novel nitrofuran compounds were synthesized. The general method involved condensation of a polyamine (putrescine, spermidine or spermine) with a nitrofuran and isolation of the required products by extraction and other techniques. The products were characterized by UV spectroscopy, H nuclear magnetic resonance and mass spectroscopy. The inhibitory activities of the novel nitrofuran compounds were determined on a range of Gram-positive and Gram-negative bacteria and fungi. Bis-5-nitrofurfurylidenylputrescine (compound I), bis-5-nitrofurfurylidenylspermine (compound II) and bis-5-nitrofurfurylidenylspermidine (compound III) showed excellent broad spectrum antibacterial activity and good antifungal activity. Bis-5-nitrofurfurylidenylethylspermidine (compound IX) also showed good antifungal activity and 5-nitrofurfurylidenylglucosamine (compound VI) good antipseudomonal activity, neither of which are exhibited by nitrofurantoin. Compounds I, II, III and 4-(N-5-nitrofurfurylidenyl)aminobenzoyl-2-acetylamino-ethylamide (compound IV) were screened for mutagenicity and genotoxicity using the Ames Salmonella mutagenicity assay and the SOS/umu genotoxicity test. Nitrofurantoin was not mutagenic against S. typhimurium strain TA98, which detects frameshift mutations, but was highly mutagenic against strain TA100, which detects base-pair substitutions. All four novel nitrofuran compounds tested were less mutagenic than nitrofurantoin in strain TA100. Similarly, all four novel nitrofuran compounds were shown to be considerably less genotoxic than nitrofurantoin in the SOSIumu test. The activities of nitrofurantoin and the four novel nitrofuran compounds I - IV were also compared in wild-type and polyamine transport- deficient mutants of E. coli K12. The novel compounds were active against transport-deficient mutants suggesting they would enter the cell via uptake mechanisms other than those determined by polyamine transport pathways.

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