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Biomedical subjects

M N Swartz

Publications and source records attributed to M N Swartz.

At least 37 records · Page 2Linked to original sources
PubMed1987

Antagonism of wild-type and resistant Escherichia coli and its DNA gyrase by the tricyclic 4-quinolone analogs ofloxacin and S-25930 stereoisomers.

The mechanism of action of the quinolone analogs ofloxacin and S-25930, which are unusual because of the presence of a third ring with an asymmetric carbon, was studied. Drug-resistant strains of Escherichia coli were selected by serial passage in the presence of ofloxacin, and a mutation was mapped near the gyrA gene of DNA gyrase. DNA gyrase containing the A subunit purified from this strain as compared with the isogenic wild-type strain exhibited increased resistance to ofloxacin, proving that the mutation was located in the gyrA gene. For S-25930, the S stereoisomer was more potent than the R isomer in inhibiting wild-type E. coli and DNA gyrase containing an A subunit isolated from this strain. Both isomers had decreased potency against the isogenic ofloxacin-resistant (gyrA) strain and its purified enzyme, but the S isomer remained more potent than the R isomer. These studies, using a combined genetic and biochemical approach, demonstrate (i) that DNA gyrase is a target of the tricyclics ofloxacin and S-25930, (ii) that serial exposure to ofloxacin can select resistance to tricyclic quinolone agents by mutation in the gyrA gene, and (iii) that the more potent antibacterial activity of S relative to R S-25930 correlates with increased activity against DNA gyrase for both wild-type and ofloxacin-resistant (gyrA) isogenic strains.

Anti-Bacterial Agents↗
PubMed1987

Dirofilaria ursi-like parasites acquired by humans in the northern United States and Canada: report of two cases and brief review.

Two cases of subcutaneous dirofilariasis acquired in Ontario and Vermont are reported. The parasites in these and eight cases previously reported from the northern United States and Canada are classified as resembling Dirofilaria ursi, a primarily subcutaneous parasite of bears, or D. subdermata of porcupines, in the same region. A distinguishing morphological feature of the D. ursi-like group is the presence of distinct longitudinal cuticular ridges regularly and widely spaced on the outer surface, and usually evident even when the worms are necrotic. In the 10 known cases, all patients were women, and the usual location of nodules containing the worms was the scalp or a covered part of the upper body where blackflies, the intermediate hosts of D. ursi, normally feed.

Animals↗
PubMed1986

Septic thrombosis of the dural venous sinuses.

From 1940 to 1984, 19 cases of septic dural-sinus thrombosis have been diagnosed at the Massachusetts General Hospital, and some 136 cases have been reported from other institutions. Septic thrombosis most frequently involves the cavernous sinuses (96 cases). Facial or sphenoid air sinus infection often precede cavernous-sinus disease. In addition to the classical signs of proptosis, chemosis, and oculomotor paralysis, isolated sixth-nerve palsy and hypo- or hyperesthesia of the fifth nerve may be found. The major pathogens associated with cavernous-sinus infection include Staphylococcus aureus, other gram-positive organisms, and anaerobes. Septic lateral-sinus thrombosis (64 cases) is almost exclusively a complication of otitis media and/or mastoid infection. Organisms causing this infection include Proteus species, Escherichia coli, S. aureus, and anaerobes. Septic thrombosis of the superior sagittal sinus (23 cases) most frequently accompanies bacterial meningitis or air sinus infection. Causative organisms include Streptococcus pneumoniae, S. aureus, other streptococci, and Klebsiella species. Because septic dural-sinus thrombosis is rare, this disease is frequently misdiagnosed. Evaluation should include lumbar puncture, air sinus films, and computed tomographic scan with contrast. Other helpful diagnostic tests may include carotid angiography, and dynamic brain scan. Orbital venography is the most definitive study in cases of chronic cavernous-sinus thrombosis. Therapy should include intravenous antibiotics and early surgical drainage of purulent exudate in the air sinuses or mastoid regions. Retrospective analysis suggests that treatment with heparin may reduce mortality in carefully selected cases of septic cavernous-sinus thrombosis. Anticoagulation is not recommended in other forms of septic dural-sinus thrombosis. Mortality in the antibiotic-era remains high, particularly in patients with septic thrombosis of the cavernous (30%) and superior sagittal (78%) sinuses.

Adolescent↗
PubMed1986

Novobiocin antagonism of amastigotes of Trypanosoma cruzi growing in cell-free medium.

Inhibitors of the enzyme bacterial topoisomerase II (DNA gyrase) were evaluated for activity against Trypanosoma cruzi (Brazil strain), based on the theoretical need for a topoisomerase II in the replication of the kinetoplast DNA network. Novobiocin (500 micrograms/ml) antagonized amastigotes of T. cruzi growing in a cell-free medium at 37 degrees C, as manifested by inhibition of multiplication, abnormal morphology of Giemsa-stained organisms, and delayed or absent growth of cells upon subculturing in a drug-free medium. In contrast, novobiocin (1,000 micrograms/ml) essentially had no effect on the multiplication and motility of epimastigotes growing in a cell-free medium at 27 degrees C. This resistance of epimastigotes represented a difference in the physiology of this morphologic stage and not in the temperature of experimentation, because novobiocin inhibited multiplication of amastigotes at 27 degrees C as well and accelerated transformation to epimastigotes. With T. cruzi growing within cultured human fibroblasts, novobiocin (200 micrograms/ml) markedly inhibited transformation of intracellular amastigotes to trypomastigotes. Clorobiocin, a structural analog of novobiocin and likewise an inhibitor of the B subunit of bacterial topoisomerase II, was five times more potent on a molar basis than novobiocin was in antagonism of amastigotes growing in a cell-free medium and did not antagonize epimastigotes. Coumermycin A1, another analog of novobiocin, and five 4-quinolone antibacterial agents, antagonists of the A subunit of bacterial topoisomerase II, inhibited neither amastigotes nor epimastigotes. These experiments indicate that novobiocin and clorobiocin represent a new structural class of drugs with activity against T. cruzi. Whether the mechanism of action of these drugs involves antagonism of a T. cruzi topoisomerase II or an unrelated target is yet to be determined.

Animals↗
PubMed1986

Genetic and biochemical characterization of norfloxacin resistance in Escherichia coli.

In Escherichia coli the frequency of spontaneous single-step mutation to high levels of resistance to the newer 4-quinolone agent norfloxacin was confirmed to be over 300-fold lower than that to the older agent nalidixic acid. Serial passage on incremental concentrations of drug was necessary to produce mutants highly resistant to norfloxacin. Genetic analysis of one such highly resistant strain identified two mutations conferring drug resistance. One mutation, nfxA, mapped around 48 min on the E. coli genetic map and was shown to be an allele of gyrA by studies demonstrating an increased drug resistance of DNA gyrase reconstituted with the gyrase A subunit isolated from the mutant strain. These findings also identified the DNA gyrase A subunit as a target of norfloxacin. The second mutation, nfxB, mapped between 20 and 22 min was associated with additional resistances to tetracycline, chloramphenicol, and cefoxitin and with decreases in outer membrane porin protein OmpF. The nfxA and nfxB mutations together accounted for most, but not all, of the norfloxacin resistance phenotype of this strain.

Bacterial Outer Membrane Proteins↗
PubMed1985

Knotting of DNA molecules isolated from deletion mutants of intact bacteriophage P4.

DNA molecules isolated from tailless phage particles (capsids) of bacteriophage P4 virl del10 are known to be knotted. We have found by electron microscopy that 80% of DNA molecules isolated from intact phage particles of P4 virl del10 also contained knots. This observation indicates that the predominant form of P4 virl del10 DNA within the intact phage particle is either knotted or in a configuration that permits knotting upon isolation. In comparison to P4 virl del10 (deleted 1000 basepairs), DNA molecules isolated from intact P4 virl del2 (deleted 650 basepairs) and P4 virl (non-deleted) contained 50% and 15% knots respectively, showing an association of decreased size of deletion of DNA with a decreased fraction of knotted genomes.

Chromosome Deletion↗
PubMed1984

Elimination of plasmid pMG110 from Escherichia coli by novobiocin and other inhibitors of DNA gyrase.

The ability of novobiocin to eliminate (cure) the wild-type plasmid pMG110 from Escherichia coli has been compared with that of other inhibitors of the gyrase B subunit and of the gyrase A subunit. Novobiocin eliminated pMG110 , producing over 99% plasmid loss at concentrations two- to eightfold below the MIC for bacterial growth. Structurally related compounds ( clorobiocin , coumermycin A1, isobutyryl novenamine , and decarbamyl novobiocin) varied in their ability to eliminate pMG110 . Higher concentrations of drugs were required to eliminate pMG110 from a gyrB( Cour ) strain, implicating DNA gyrase in the curing phenomenon. For these drugs, the ratio of the concentration effecting maximal plasmid elimination to the MIC varied from 0.16 to 1.1, indicating that curing cannot be explained simply by inhibition of a pool of DNA gyrase equally available for replication of the bacterial chromosome and the plasmid DNA molecule. Inhibitors of the gyrase A subunit, nalidixic acid and oxolinic acid, eliminated pMG110 only to variable low levels. The differences in the ability of the gyrase A and B subunit antagonists to eliminate plasmids are discussed.

Escherichia coli↗
PubMed1984

Pasteurella multocida infections. Report of 34 cases and review of the literature.

Pasteurella multocida, a small, gram-negative coccobacillus , is part of the normal oral flora of many animals, including the dog and cat. P. multocida is the etiologic agent in a variety of infectious disease syndromes. We have reported 34 cases of infection caused by P. multocida and have reviewed the English literature. P. multocida infections may be divided into three broad groups: 1. Infections resulting from animal bites and scratches : The most common infections caused by P. multocida are local wound infections following animal bites or scratches . Cats are the source of infection in 60 to 80% of cases and dogs in the great majority of the remainder. Local infections are characterized by the rapid appearance of erythema, warmth, tenderness, and frequently purulent drainage. The most common local complications are abscess formation and tenosynovitis. Serious local complications include septic arthritis proximal to bites or scratches , osteomyelitis resulting from direct inoculation or extension of cellulitis, and the combination of septic arthritis and osteomyelitis, most commonly involving a finger or hand after a cat bite. 2. Isolation of P. multocida from the respiratory tract: The isolation of P. multocida from the respiratory tract must be interpreted differently than its isolation from other systemic sites. Most commonly P. multocida found in the respiratory tract is a commensal organism in patients with underlying pulmonary disease, but serious respiratory tract infections including pneumonia, empyema, and lung abscesses may develop. Most patients with respiratory tract colonization or infection have a history of animal exposure. 3. Other systemic infections: P. multocida is recognized as a pathogen in a variety of systemic infections including bacteremia, meningitis, brain abscess, spontaneous bacterial peritonitis, and intra-abdominal abscess. P. multocida often acts as an opportunistic pathogen with a predilection for causing bacteremia in patients with liver dysfunction, septic arthritis in damaged joints, meningitis in the very young or elderly, and pulmonary colonization or invasion in patients with underlying respiratory tract abnormalities.(ABSTRACT TRUNCATED AT 400 WORDS)

Abscess↗
PubMed1983

Rapid method for screening large numbers of Escherichia coli colonies for production of plasmid-mediated beta-lactamases.

A rapid, simple assay for screening large numbers of Escherichia coli colonies for production of certain plasmid-mediated beta-lactamases (including TEM-1, TEM-2, HMS-1, SHV-1, OXA-1, PSE-1, PSE-4, and CEP-2) is described. The technique, a modification of the method of Slack et al. for detection of beta-lactamase in limited numbers of Haemophilus influenzae clinical isolates (Lancet ii:906, 1977), uses filter paper impregnated with benzylpenicillin and a pH indicator dye (bromocresol purple) that changes color in the presence of beta-lactamase activity. The test paper is briefly applied to an agar surface containing bacterial colonies which are subsequently scored individually on the paper by color: yellow indicates the presence of beta-lactamase, dark green its absence, and variegation (yellow and dark green) a mixed population. Concordance of the results of this assay with those of replica plating for antibiotic resistance was over 99%. Hundreds of colonies per plate can be scored quickly and remain viable for further evaluation. The assay appears to be useful for studies of the stability of plasmids encoding beta-lactamases and in cloning with vectors such as pBR322 in which insertion of DNA fragments can be detected by inactivation of the beta-lactamase gene. Whenever the assay is to be used, results should always be confirmed initially by another method, such as replica plating, because the test paper assay does not detect three beta-lactamases (OXA-2, OXA-3, and PSE-2) and also would miss intrinsic penicillin resistance.

Drug Resistance, Microbial↗
PubMed1983

Novobiocin-induced elimination of F'lac and mini-F plasmids from Escherichia coli.

Novobiocin eliminated (cured) F'lac and three low-copy-number mini-F plasmids (pML31, pMF21, and pMF45) from Escherichia coli to different extents. F'lac was cured 0 to 3%. pML31, whose replication region is contained on the 9-kilobase f5 EcoRI restriction enzyme fragment of F, was eliminated 10 to 92%. pMF21, deleted of the origin of mini-F replication at 42.6 kilobases on the F map and known to initiate from an origin at 45.1 kilobases, and its closely related derivative pMF45 were cured to the greatest extent (greater than 97%). pMF45 was eliminated from a wild-type bacterial strain but not from an isogenic novobiocin-resistant gyrB mutant strain, indicating involvement of the B subunit of DNA gyrase in the curing phenomenon. The number of bacteria containing pMF45 halved with each generation of growth in the presence of novobiocin, as is predicted for complete inhibition of plasmid DNA replication.

DNA Replication↗
PubMed1983

Circulating immune complexes in prosthetic valve endocarditis.

Using the Raji cell radioimmunoassay, we have determined circulating immune complex (CIC) levels in 36 patients with prosthetic valves during 38 episodes of fever. Fever resulted from prosthetic valve endocarditis (PVE) in 27 instances and from other causes in 11 instances. Peak initial CIC levels higher than 100 micrograms/mL occurred more frequently in the group with PVE, while peak initial CIC values less than 30 micrograms/mL were more frequent in the control group. Circulating immune complex levels fell substantially with completion of antibiotic therapy in 28 (78%) of the patients with PVE. Late CIC elevations were associated with drug-related rashes and replacement of persistently infected prostheses. Our data suggest that the predictive value of measurement of CIC levels in patients with fever and prosthetic valves is in excluding PVE in patients with CIC levels persisting below 30 micrograms/mL.

Antigen-Antibody Complex↗
PubMed1982

Effects of novobiocin, coumermycin A1, clorobiocin, and their analogs on Escherichia coli DNA gyrase and bacterial growth.

Novobiocin, coumermycin A1, and clorobiocin, structurally related compounds that antagonize the B subunit of the essential bacterial enzyme DNA gyrase, were compared with 18 of their analogs for the inhibition of Escherichia coli DNA gyrase supertwisting activity in vitro and of bacterial multiplication. This family of compounds has a 4-hydroxy-8-methylcoumarin core substituted in the 7 and 3 positions. Important for enzyme inhibition in vitro is a 7 ether linkage to a 3'-substituted noviose sugar. The 3'-ester-linked 5-methylpyrrole, found in the coumermycin series, conferred at least 10-fold more inhibitory activity than did the similarly linked amide, found in the novobiocin series; lack of the pyrrole and amide results in the loss of inhibitory activity. Of many aryl and alkyl substituents linked as an amide at the 3 position, the 4-hydroxyl-3-(3-methyl-2-butenyl)benzoic acid moiety, found in novobiocin and clorobiocin, and the reduplication of the coumarin-noviose-5-methylpyrrole, found in coumermycin A1, were most effective in gyrase inhibition. In vivo, the ability of these compounds to inhibit the growth of E. coli varied greatly. The enhanced inhibition of gyrase in vitro conferred by a 5-methylpyrrole relative to an amide in the 3'-noviose position was reflected in inhibition of bacterial multiplication. Several substitutions at the 3 position of the coumarin core conferring similar antagonism of gyrase in vitro resulted in substantially different inhibitory activities for E. coli, suggesting that these moieties at the 3 position affect drug access to the intracellular target. This target was shown for isobutyryl PNC-NH2 (PNC-NH2 is 3-amino-4-hydroxy-8-methyl-7-[3-O-(5-methyl-2-pyrrolylcarbonyl)noviosyloxy] coumarin) and confirmed for novobiocin, coumermycin A1, and clorobiocin to be in the B subunit of DNA gyrase.

Aminocoumarins↗
PubMed1982

Antagonism of the B subunit of DNA gyrase eliminates plasmids pBR322 and pMG110 from Escherichia coli.

The constructed plasmid pBR322 and the native plasmid pMG110 were eliminated (cured) from growing Escherichia coli cells by the antagonism of the B subunit of the bacterial enzyme DNA gyrase. The antagonism may be by the growth of cells (i) at semipermissive temperatures in a bacterial mutant containing a thermolabile gyrase B subunit or (ii) at semipermissive concentrations of coumermycin A1, an antibiotic that specifically inhibits the B subunit of DNA gyrase. The kinetics of plasmid elimination indicate that plasmid loss occurs too rapidly to be explained solely by the faster growth of that plasmid-free bacteria and, therefore, represents interference with plasmid maintenance.

Aminocoumarins↗