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Biomedical subjects

L J Piddock

Publications and source records attributed to L J Piddock.

At least 91 records · Page 5Linked to original sources
PubMed1990

Correlation of quinolone MIC and inhibition of DNA, RNA, and protein synthesis and induction of the SOS response in Escherichia coli.

The effects of nalidixic acid and four fluoroquinolones on DNA, RNA, and protein synthesis in the presence and absence of 20 mg of chloramphenicol per liter were examined by comparing the killing kinetics, MIC, morphological response, and maximum concentration to induce recA in Escherichia coli. All agents demonstrated paradoxical killing kinetics, in that above an optimum concentration the rate of bactericidal action was slower. Filamentation of E. coli AB1157 was observed with all quinolones up to the optimum bactericidal concentration. Addition of chloramphenicol reduced the bactericidal activity, inhibited filamentation, and abolished recA induction, but it had no effect on DNA synthesis inhibition by any of the agents. Excellent correlation was obtained between the concentration required to inhibit DNA synthesis by 50%, the MIC, the maximum concentration to induce recA, and the optimum bactericidal concentration. Evidence from this study and previously published data suggest that the primary mechanism of action of quinolones is independent of the SOS response and does not require active protein synthesis; however, induction of recA and SOS responses is consequential and enhances cell death.

Anti-Infective Agents↗
PubMed1990

Mechanism of action of lomefloxacin.

The inhibition of supercoiling activity of reconstituted Escherichia coli DNA gyrase by lomefloxacin, ciprofloxacin, and norfloxacin was determined. The concentrations of quinolones needed to inhibit DNA synthesis in Escherichia coli, Enterobacter cloacae, Serratia marcescens, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus were also measured. The kinetics of uptake of [14C]lomefloxacin and unlabeled lomefloxacin into whole cells of E. coli KL-16 and S. aureus NCTC 8532 and the induction of RecA in E. coli GC2241 were assayed. All strains had wild-type susceptibilities to quinolones. The concentration of quinolones needed to inhibit DNA synthesis by 50% correlated with the MIC for members of the family Enterobacteriaceae and P. aeruginosa. The concentration of quinolones needed to inhibit DNA synthesis by 50% for late-logarithmic-phase S. aureus also correlated with the MIC, unlike the data from early-logarithmic-phase cultures. E. coli and S. aureus showed a similar pattern of uptake kinetics of [14C]lomefloxacin and unlabeled lomefloxacin, indicating that the difference in the susceptibilities of the two species is probably due to different target site affinities. Essentially, lomefloxacin was less active than ciprofloxacin and ofloxacin and had activity similar to those of norfloxacin and enoxacin.

Anti-Infective Agents↗
PubMed1989

The killing action of fleroxacin upon Bacteroides fragilis.

The killing kinetics of fleroxacin against four strains of Bacteroides fragilis were investigated. Viable counts were determined from 0 to 24 h after exposure to fleroxacin at multiples of the MIC. A one to three log reduction in viable count was observed after 2 h at 8 mg/l fleroxacin, and a more rapid rate of killing was seen at greater concentrations of the antimicrobial agent. An increase in cell length was observed at concentrations at and above the MIC from 2 h after exposure. The presence of a bacteriostatic concentration of chloramphenicol had negligible influence on viability but inhibited cell elongation.

Anti-Bacterial Agents↗
PubMed1989

Activity of FCE 22101 against methicillin-resistant Staphylococcus aureus and affinity for penicillin binding proteins.

The susceptibility of 47 clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) to FCE 22101, imipenem and methicillin was determined with Iso-Sensitest media, with or without NaCl and with incubation at 30 degrees and 37 degrees C and for 24 and 48 h. All strains had a MIC 8 mg/l of methicillin under at least one of the culture conditions. The MIC90 of FCE 22101 was 1 mg/l, and that of imipenem 16 mg/l. The affinity of FCE 22101 for the penicillin-binding proteins (PBPs) of five clinical isolates of MRSA and S. aureus 13136 p-m+ was examined in envelope preparations and whole cell assay under the growth conditions listed above. PBP 2' was detected in all MRSA, and the clinical isolates had an I50 of 4 mg/l FCE 22101. These in-vitro data suggest that FCE 22101 may be active against MRSA in clinical use.

Anti-Bacterial Agents↗
PubMed1989

The effect of mutations in the SOS response on the kinetics of quinolone killing.

The SOS response is induced in Escherichia coli by agents that damage DNA, such as quinolone antibiotics. It has been proposed that induction of the SOS response by these agents may have a role in the mechanism of quinolone action. SOS mutants derived from Escherichia coli AB1157 were investigated by susceptibility testing and killing kinetic studies at various quinolone concentrations to determine whether SOS response induction was protective or damaging to quinolone-treated bacteria. Susceptibility testing showed some differences between the SOS mutants, but killing kinetic studies demonstrated further differences, some of which could be explained with respect to the SOS phenotype. The effect of ciprofloxacin and nalidixic acid on the mutants cannot be explained with respect to the SOS phenotype, although the presence of a defective SOS response makes the bacteria less sensitive to the action of these agents. Evidence is provided that the induction of the SOS response may be protective to fleroxacin and enoxacin treated bacteria. These results suggest that quinolones may not have a common mechanism of action, as was first thought.

4-Quinolones↗
PubMed1988

The selection and frequency of streptococci with decreased susceptibility to ofloxacin compared with other quinolones.

Three strains each of Streptococcus pneumoniae, Lancefield group A streptococci, Lancefield group B streptococci and Lancefield group D streptococci were examined for the frequency of spontaneous mutation to give decreased susceptibility at two, four and six times the minimum inhibitory concentration of ofloxacin, ciprofloxacin, enoxacin and norfloxacin. Any putative mutants were examined for stability of resistance and susceptibility to all quinolones in the study, erythromycin and benzyl penicillin. All strains yielded mutants to twice the MIC of each quinolone at a frequency associated with a mutation at a single gene. Each species in the study responded differently at four and six times the MIC of each quinolone. Group B streptococci yielded most mutants and resistant Str. pneumoniae were the most difficult to select. Most mutants were cross-resistant to quinolones only, probably owing to an altered DNA gyrase. Fewer resistant mutants of Str. pneumoniae were selected using ofloxacin compared to ciprofloxacin.

Anti-Infective Agents↗
PubMed1987

Cefoxitin resistance in Bacteroides species: evidence indicating two mechanisms causing decreased susceptibility.

Clinical isolates of Bacteroides species resistant to cefoxitin (not due to beta-lactamase) were obtained from two sources and examined for PBP affinity (to cefoxitin) and outer membrane proteins. Mutants of Bacteroides fragilis with decreased susceptibility to cefoxitin were obtained in the laboratory with the mutagen N-methyl-N'-nitro-N-nitrosoguanidine. No spontaneous mutants resistant to cefoxitin could be selected. Changes in the affinity of PBP 1 or PBP 2 were correlated with a decrease in susceptibility to cefoxitin. Two clinical isolates showing decreased affinity of PBPs for cefoxitin also showed outer membrane protein changes with a protein of 49-50,000 daltons apparently absent. Three strains did not have altered PBP affinity or altered outer membrane protein profile, one strain being a laboratory mutant.

Bacterial Outer Membrane Proteins↗
PubMed1987

The effect of imipenem on strains of Enterobacteriaceae expressing Richmond & Sykes class I beta-lactamases.

Fourteen strains of Enterobacteriaceae producing Richmond & Sykes Class I beta-lactamase were studied. The ability of cefoxitin and imipenem to induce beta-lactamase production (reversible derepression) and to select stably derepressed mutants in these strains was assessed. beta-Lactamase induction by cefoxitin and imipenem was demonstrated by the disc diffusion technique in all strains. Cefoxitin selected stably derepressed mutants for all strains in broth cultures, but in an identical experiment imipenem did not. The susceptibility of each strain and its stably derepressed mutant (selected with cefoxitin) to a range of beta-lactam antibiotics was then ascertained. The stably derepressed mutants exhibited decreased susceptibility to all antibiotics tested except imipenem. The decrease in susceptibility varied between strains and between antibiotics but reached a maximum of a 256-fold decrease. The beta-lactamase activity of selected stably derepressed mutant strains showed at least a 600-fold increase in activity. Imipenem would therefore seem an appropriate choice for therapy of infections caused by this group of organisms, as it is active against derepressed mutants and unlikely to select any such strains during therapy.

Anti-Bacterial Agents↗
PubMed1987

In vitro activity of CGP 31608, a new penem.

The in vitro activity of CGP 31608, a semisynthetic penem derivative, was compared with that of Sch 34343, imipenem, cefoxitin, cefuroxime, and ceftazidime and other beta-lactams, when appropriate, against 628 recent isolates and other beta-lactam-resistant strains. The MICs of CGP 31608 against 90% of the members of the family Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Neisseria spp., Bacteroides spp., Clostridium spp., staphylococci, and Streptococcus pneumoniae were between 0.25 and 8 micrograms/ml. The susceptibility of beta-lactamase-producing strains and known porin mutants of the Enterobacteriaceae suggests that CGP 31608 is resistant to many important beta-lactamases (including the mutationally derepressed chromosomal enzymes) and is not excluded from the bacterial cell in strains expressing these known porin mutations. Generally, CGP 31608 was less active than imipenem, Sch 34343, and the cephalosporins, except against Pseudomonas aeruginosa. The activity of CGP 31608 against Staphylococcus aureus (including methicillin-resistant strains) was greater than that of the cephalosporins. The major target site in Escherichia coli K-12 for CGP 31608 was penicillin-binding protein 2. The serum protein binding of 5 micrograms of CGP 31608 per ml was 14%, and serum had little effect on activity.

Anti-Bacterial Agents↗
PubMed1986

In vitro studies of S-25930 and S-25932, two new 4-quinolones.

The in vitro activity of S-25930 and S-25932 was compared with that of ciprofloxacin, norfloxacin and nalidixic acid against 740 clinical isolates. The data indicate that S-25930 was more active against Enterobacteriaceae than S-25932 and the latter was more active against gram-positive species. A study of clinical isolates resistant to chemically non-related classes of antibiotics revealed no cross-resistance. Nalidixic acid resistant Enterobacteriaceae showed an eight-fold decrease in susceptibility to the new agents. The killing kinetics of both compounds were good, S-25932 having an optimal bactericidal effect at a concentration of 0.5 mg/l. The data suggests that both agents are effective broad spectrum antibiotics.

Anti-Bacterial Agents↗
PubMed1986

Cross-resistance of nalidixic acid resistant Enterobacteriaceae to new quinolones and other antimicrobials.

One hundred urine isolates Enterobacteriaceae screened for resistance to 30 micrograms nalidixic acid by disc diffusion test were examined by MIC determination for in vitro susceptibility to nalidixic acid, ciprofloxacin, enoxacin, gentamicin, nitrofurantoin, trimethoprim, cephalexin and ceftazidime. Those resistant to nalidixic acid and also gentamicin or a cephalosporin were further examined to determine the mechanism of resistance. Compared to the total urine isolates of Enterobacteriaceae from the same time period, this population as a whole was less susceptible to all antimicrobials tested except gentamicin. Strains that exhibited multiple resistance had the conventional mechanisms of resistance to those antimicrobials. No multiply resistant strains had a permeability barrier due to outer membrane protein alterations causing cross-resistance to chemically unrelated classes of antimicrobials.

Anti-Bacterial Agents↗
PubMed1986

Properties of the penicillin-binding proteins of four species of the genus Bacteroides.

The penicillin-binding proteins (PBPs) of four species of the genus Bacteroides were examined in cell envelope preparations from exponentially growing cultures and intact cells. Upon examination by sodium dodecyl sulfate-polyacrylamide electrophoresis, three major high-molecular-weight PBPs (molecular weight, 58,000 to 82,000) were resolved, and low-molecular-weight PBPs were seen in all strains except Bacteroides fragilis. The sporadic appearance of PBP 4 in B. fragilis (molecular weight, approximately 45,000) was shown not to be influenced by the concentration of free iron available in the medium or by the stage of growth at which the batch culture was harvested. No PBP that was inhibited by an aerobic environment was demonstrated. The affinity of 35 beta-lactam antibiotics for the PBPs from envelope preparations was examined and correlated with the morphological response. Most compounds bound initially to PBP 2 and then PBP 1, correlating with a primary response of filamentation and then spheroplasting and lysis. Compounds such as clavulanic acid bound to PBP 3 at concentrations causing round cells. Based on the data from this study, it is proposed that the three high-molecular-weight PBPs of Bacteroides fragilis, Bacteroides vulgatus, Bacteroides thetaiotaomicron, and Bacteroides ovatus correlate to the three high-molecular-weight PBPs of Escherichia coli and that the PBPs of Bacteroides species perform the same enzymic role in cell wall biosynthesis as their counterparts in E. coli. Therefore, the components of PBP 1 are involved in cell elongation, PBP 2 is involved in septum formation, and PBP 3 is involved in maintenance of cell shape (i.e., PBP 2 in Bacteroides spp. = PBP 3 in E. coli, and PBP 3 in Bacteroides spp. = BPB 2 in E. coli).

Anti-Bacterial Agents↗
PubMed1986

In vitro activity of Ro 15-8074 and Ro 19-5247, two orally administered cephalosporin metabolites.

The activity of two iminomethoxy aminothiazoly cephalosporins, Ro 15-8074 and Ro 19-5247, was compared with that of other beta-lactams against a total of 491 bacterial strains. Both were highly active (MIC for 90% of the strains tested [MIC 90], less than or equal to 2 micrograms/ml) against the majority of the members of the family Enterobacteriaceae, Haemophilus influenzae, Neisseria spp., and Streptococcus pneumoniae, being at least 16-fold more active than cephalexin and 8-fold more active than cefuroxime. There was no activity against Pseudomonas aeruginosa and poor activity against Morganella morganii (in the case of Ro 15-8074), Enterobacter sp., and Citrobacter sp. Staphylococcus aureus was moderately susceptible to Ro 19-5247 (MIC90, 8 micrograms/ml), but Ro 15-8074 was eightfold less active. The protein binding of the two compounds at 5 micrograms/ml was 9.1% for Ro 15-8074 and 69.9% for Ro 19-5247. The major target site for the two cephalosporins was PBP 3.

Bacteria↗
PubMed1985

The in-vitro activity of Ro 17-2301, a new monobactam, compared with other antimicrobial agents.

The susceptibility of 554 recent clinical isolates and known resistant bacterial strains to the new monocyclic beta-lactam Ro 17-2301 were studied and compared to that to other beta-lactams (including aztreonam and temocillin) and gentamicin. Ro 17-2301 had a high degree of activity against the Enterobacteriaceae (MIC90 less than or equal to 0.25 mg/l) being similar or slightly more active than aztreonam and ceftazidime. Strains of Acinetobacter spp. (MIC90 16 mg/l). Haemophilus influenzae strains (including beta-lactamase producers) were more susceptible (MIC90 0.5 mg/l) than those of Neisseria gonorrhoeae (MIC90 4 mg/l); against these latter two groups of isolates aztreonam was more active (MIC90 0.12 mg/l). Both aztreonam and Ro 17-2301 had little activity against Gram-positive cocci with the exception of Streptococcus pneumoniae for which the MIC90 of RO 17-2301 was 16 mg/l. Ro 17-2301 had modest activity against Bacteroides fragilis. The MBC of Ro 17-2301 was very similar to the MIC and the addition of human serum had little effect on the amount of the compound. The mean serum protein binding was 26.3%. A study of the penicillin binding protein affinity of Ro 17-2301 in a strain of Escherichia coli showed PBP 3 to be the primary target. The morphological response to exposure to Ro 17-2301 was filamentation followed by lysis after prolonged exposure.

Anti-Bacterial Agents↗