Investigation of the beta-lactamase stability of ceftazidime and eight other new cephalosporin antibiotics.
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Bacterial Infections↗
Biomedical subjects
I N Simpson
Publications and source records attributed to I N Simpson.
Selection for increased penicillin titre following hybridization of divergent lines of Aspergillus nidulans.
Sexual hybridization of two divergent lines of Aspergillus nidulans, which had been selected for increased penicillin titre through successive cycles of mutagenesis, released considerable variation for this character. The recovery of segregants with titres equivalent to that of the unselected ancestor suggested that mutations in different genes had been selected in the two lines. However, complementary segregants with substantially improved titres were not found, indicating interactions, probably of a duplicate nature, among the induced mutations. All the genetic variation released by hybridization was fixed following two generations of selection for high titre, but only a small gain over the initial selection lines was achieved. Hybridization of divergent strains has been widely advocated as a means of strain development. The failure to achieve the anticipated gains in this programme is attributed primarily to the unfavourable interactions amongst the induced mutations. Whether similar interactions occur generally in crosses between strains selected by mutagenesis remains to be established and will be an important factor in determining the contribution of recombinational approaches to yield improvement.
Analysis of Variance↗
Genetics of penicillin titre in lines of Aspergillus nidulans selected through recurrent mutagenesis.
Genetic analyses of mutations for increased penicillin titre were carried out on two strains of Aspergillus nidulans isolated after independent programmes of recurrent mutation and selection, similar to those used industrially for strain improvement. Both selected strains were stable in terms of colony morphology and penicillins titre. Backcrosses to the unselected ancestor indicated that the increased yield of each strain was due to an induced polygenic system with both additive and non-additive gene action. The titre-increasing mutations in one strain (A6-9) were recessive to their wild-type alleles, while those in the other (B6-27) were either semi-dominant or showed ambidirectional dominance. The diploid between A6-9 and B6-27 had a titre less than either component haploid, suggesting that the mutations in the two strains involved different genes. Strain B6-27 carried a translocation between chromosomes III and VII which had been induced during the selection programme. This investigation complements previous work on the genetics of penicillin production in A. nidulans and Penicillium chrysogenum and the results are directly relevant to industrial strain improvement by hybridization of divergent strains.
Alleles↗
Principal beta-lactamases responsible for resistance to beta-lactam antibiotics in urinary tract infections.
Two independent surveys have been conducted to determine the prevalent bacterial species and beta-lactamase types present in clinical populations of gram-negative, ampicillin-resistant isolates. A total of 208 isolates (112 from Nottingham Hospital and 96 from Charing Cross Hospital), all of which had been collected from out-patients suffering from urinary tract infections, were investigated. The incidence of ampicillin-resistant isolates (minimum inhibitory concentrations, 8 micrograms/ml) was 24.1% and 18.8% within the Nottingham and Charing Cross samples, respectively. The surveys gave similar results within the ampicillin-resistant samples. Escherichia coli was the prevalent bacterial species (52.9%), followed by Klebseilla pneumoniae (30.3%). The majority of isolates, at least 54.8% and possibly as high as 74.5%, owed their principal beta-lactamase activity to enzymes mediated by R-plasmids. The most prevalent beta-lactamases were TEM-1 (53.3%), SHV-1 (30.9%), and OXA-1 (11.5%). Positive associations were found between E. coli and TEM-1 or OXA-1 and between K. pneumoniae and SHV-1.
Ampicillin↗
Induced quantitative variation for penicillin titre in clonal populations of Aspergillus nidulans.
The variation in penicillin titre within populations of cultures of Aspergillus nidulans derived from untreated conidia and from conidia treated with ethyl methanesulphonate (EMS), near-ultraviolet light in the presence of 8-methoxypsoralen (8MOP) or N-methyl-N'-nitro-N-nitrosoguanidine (NTG), each at several dose levels, was determined. Both mutagentreated and untreated populations showed a continuous distribution of pencillin titres. The population mean titre of the mutagenized populations was decreased and the range of titres was increased relative to those of the control populations. No differences between sister cultures could be detected in three untreated populations, but nine out of ten populations derived from mutagenized conidia showed significant variation for penicillin titre. In general the magnitude of this induced variation increased with increasing dosage of the mutagen. Comparisons at fixed survival levels indicate that 8MOP mutagenesis is less effective for the induction of variation in penicillin titre than EMS or NTG mutagenesis. A statistical procedure was adopted to classify the survivors as unchanged cultures ('0'), titre-increasing mutants ('+') or titre-decreasing mutants ("-"). The frequency of both '+' and '-' mutants increased following mutagenesis, with NTG being the most active of the three mutagens. Over all treatments, these two mutant classes were recovered with equal frequency. The frequency of "+" mutants was largely independent of mutagen dose, within the ranges used, and moderate treatments (around 10% survival) gave as high or higher frequencies than more extreme doses. All three mutagens, and in particular NTG, produced morphological mutants. These contained an increased frequency of titre-decreasing mutants, but increases in titre appeared to be independent of changes in colony morphology. Estimates based on the observed frequencies of penicillin titre mutants suggest that several hundred genes are potentially capable of affecting this continuous variable.
Aspergillus nidulans↗
Recurrent mutation and selection for increased penicillin titre in Aspergillus nidulans.
Recurrent mutation and selection has been used to increase penicillin titre in two closely related strains of Aspergillus nidulans. A selection programme was initiated from each of the two strains (programmes A and B) and continued through six cycles of mutation and selection. Near-ultraviolet light in conjuction with 8-methoxypsoralen was employed as the sole mutagen throughout programme A and ethyl methanesulphonate as the sole mutagen throughout programme B. Excluding the first cycle of A, where only 50 strains were assayed, the selection programmes were identical. In each programme, 100 survivors were assayed for penicillin titre after each mutagenic treatment and, on the basis of a single yield test, the best five strains were picked and carried forward to the next cycle. In both selection programmes, a near 300% increase in penicillin titre was achieved. This yield advance illustrates the effectiveness for strain development of experimental designs involving successive cycles of mutagenesis with a single-stage screen and the selection of the top few percent survivors in each cycle.
Aspergillus nidulans↗