In vivo studies with sisomicin, gentamicin and tobramycin

Shadomy, Smith; Utz, C.; Shadomy, H. Jean

doi:10.1007/bf01646965

Cited by 5 publications

(5 citation statements)

References 8 publications

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“…Similar relationships between the three latter antibiotics have been described by previous investigators (1,4,6,8). Heart blood and peritoneal cultures obtained from infected animals demonstrated that the peritoneal infection model was almost uniformly followed by bacteremia.…”

Section: Discussionsupporting

confidence: 85%

Comparison of 5-Episisomicin (Sch 22591), Gentamicin, Sisomicin, and Tobramycin in Treatment of Experimental Pseudomonas Infections in Mice

Goering

Sanders

1978

Antimicrob Agents Chemother

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Sch 22591 (5-episisomicin), gentamicin, sisomicin, and tobramycin were compared for their ability to protect mice from lethal intraperitoneal challenge with 12 Pseudomonas strains, all susceptible to each of the aminoglycosides (minimal inhibitory concentrations and minimal bactericidal concentrations were -6.2 ,ug/ml). Median 50% protective doses were 5.8, 6.4, 7.7, and 17.8 mg/kg for Sch 22591, tobramycin, sisomicin, and gentamicin, respectively. Those for Sch 22591 were significantly lower than gentamicin in five protection tests and significantly lower than both gentamicin and tobramycin in one test. Microbial analysis of the therapeutic effect indicated that protection from lethality by each of the four aminoglycosides was associated with either a complete eradication or a reduction in the number of challenge bacteria in both the heart blood and peritoneum. In rare instances, challenge isolates exhibiting decreased susceptibility to one or more of the aminoglycosides were recovered from animals. However, this in vivo selection of resistance did not appear related to either the aminoglycoside used in therapy or the outcome of therapy, and resistant isolates were recovered as frequently from untreated animals as from those receiving one of the four aminoglycosides.Sch 22591 (5-episisomicin) is a new semisynthetic aminoglycoside structurally similar to sisomicin. In vitro, Sch 22591 has been shown to possess greater activity than gentamicin, sisomicin, tobramycim, amikacin, netilmicin, or kanamycin against a variety of gram-positive and gram-negative organisms (5, 7). In vivo, Sch 22591 also appears to be more active than other aminoglycosides in the treatment of mice infected with Pseudomonas aeruginosa (7). In view of the greater activity of Sch 22591 over other aminoglycosides, studies were performed to evaluate this compound more extensively in vivo. These studies were designed to compare Sch 22591, sisomicin, gentamicin, and tobramycin for their ability to (i) protect mice lethally infected with a variety of Pseudomonas species, (ii) eradicate or reduce the number of the challenge bacteria in the heart blood and peritoneum of infected mice, and (iii) select aminoglycosideresistant bacteria in vivo. MATERIALS AND METHODSChallenge strains. All strains were recent clinical isolates from St. Joseph Hospital or the Veterans Administration Hospital, Omaha, Nebr.Determination of virulence of challenge bacterial strains. Strains were grown for 16 h on brain heart infusion agar slants (Difco Laboratories). These cultures were used to inoculate Mueller-Hinton broth (Difco), which was then incubated with shaking at

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Section: Discussionsupporting

confidence: 85%

Comparison of 5-Episisomicin (Sch 22591), Gentamicin, Sisomicin, and Tobramycin in Treatment of Experimental Pseudomonas Infections in Mice

Goering

Sanders

1978

Antimicrob Agents Chemother

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“…"Partially purified rat liver DHFR (EC 1.5.1.3) was prepared by the method of Bertino and Fischer24 and assayed spectrophotometrically by a previously published method.15 6 Defined as the final concentration of inhibitor in the assay system necessary to reduce the enzymatic reaction rate to 50% of the uninhibited rate, /so values were determined by conducting assays in duplicate at ethylbenzylamino analogues (29 and 30) by the zone B analysis method16 appropriate for tight-binding enzyme inhibitors, and assuming a Km value of 0.2 µ for dihydrofolate,17 gave figures of 0.009 ± 0.002 (nM) and 0.04 ± 0.03 (nM), respectively. Metoprin (2) in comparison gave a K{ of 0.12 ± 0.04 (nM) in the same test. Interestingly, transposing the nitro and TV-alkylbenzylamino substituents to furnish the isomeric analogues (36 and 37) reduced activity considerably.…”

Section: Biological Resultsmentioning

confidence: 75%

“…In an earlier paper2 we reported on the chemical and enzyme-inhibitory properties of 2,4-diamino-2-(azidoaryl)-6-alkylpyrimidines and presented evidence that the lipophilic but biolabile azido group can modulate the properties of this novel type of dihydrofolate reductase (DHFR) inhibitor. One compound, the ethanesulfonic acid salt of 2,4-diamino-5-(3-azido-4-chlorophenyl)-6-ethylpyrimidine (1; MZPES)3 has completed Phase I clinical evaluation as an antitumor agent and been shown to have a biological half-life (t1/2) in humans of 35 h, significantly less than the t1/2 (>200 h)4 of the structurally related but extremely toxic agent metoprin [2,4-diamino-5-(3,4-dichlorophenyl)-6-methylpyrimidine] (2).…”

mentioning

confidence: 99%

Structural studies on bioactive compounds. 8. Synthesis, crystal structure and biological properties of a new series of 2,4-diamino-5-aryl-6-ethylpyrimidine dihydrofolate reductase inhibitors with in vivo activity against a methotrexate-resistant tumor cell line

Griffin¹,

Meek²,

Schwalbe³

et al. 1989

J. Med. Chem.

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A series of 2,4-diamino-5-aryl-6-ethylpyrimidines embracing basic substituents in the 5-aryl ring was synthesized and evaluated for inhibitory activity against rat liver dihydrofolate reductase (DHFR). Maximal enzyme inhibition was observed for compounds bearing a benzylamino (19) or N-alkylbenzylamino substituent (29 and 30) in the 4-position of the phenyl ring and a nitro group in the 3-position, the corresponding 3-amino, 3-azido, or unsubstituted analogues proving only weakly active or inactive as DHFR inhibitors. Selected compounds were also screened in vivo against a methotrexate-resistant tumor, the M5076 murine reticulosarcoma, and antitumor activity in general paralleled activity against DHFR, the (3,4-dichlorobenzyl)amino analogue 26 proving the least toxic compound to exhibit significant antitumor activity. The X-ray crystal structure of the ethanesulfonic acid salt of the N-methylbenzylamino compound 29 has been determined to facilitate future molecular modeling studies in this new series of DHFR inhibitors.

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“…A For other information on aminoglycoside-aminocyclitol inactivating enzymes, the following references may be consulted: Weinstein (1967Weinstein ( , 1973, Davies (1971), Tseng el al. (1972), Bryan et al (1974, Jacoby (1974), Kabins et al (1974), Lundback & Nordstrom (1974), O'Hara et al (1974), Lacey (1975), Sykes & Morris (1975), Stewart & Bodey (1975), Neu (1976), Sanders & Sanders (1976), Shadomy et al (1976.…”

Section: (Ii) a Rninog!vcoside-aminocyclitoi Antibioticsmentioning

confidence: 99%

“…Such crude preparations could, in time, possibly be replaced by a purified version. Such a technique would overcome the criticisms of the currently used methods of determining MBC values or estimating survival numbers where no thought is given to the possibility of the effect of the antibiotic on recovery of treated cells (Linzenmeier et al 1976;McAllister & Tait 1976;Sanders & Sanders 1976;Shadomy et al 1976).…”

Section: (Ii) a Rninog!vcoside-aminocyclitoi Antibioticsmentioning

confidence: 99%

Microbiological Applications of the Inactivation of Antibiotics and Other Antimicrobial Agents

Russell

Ahonkhai

Rogers

1979

Journal of Applied Bacteriology

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In vivo studies with sisomicin, gentamicin and tobramycin

Cited by 5 publications

References 8 publications

Comparison of 5-Episisomicin (Sch 22591), Gentamicin, Sisomicin, and Tobramycin in Treatment of Experimental Pseudomonas Infections in Mice

Comparison of 5-Episisomicin (Sch 22591), Gentamicin, Sisomicin, and Tobramycin in Treatment of Experimental Pseudomonas Infections in Mice

Structural studies on bioactive compounds. 8. Synthesis, crystal structure and biological properties of a new series of 2,4-diamino-5-aryl-6-ethylpyrimidine dihydrofolate reductase inhibitors with in vivo activity against a methotrexate-resistant tumor cell line

Microbiological Applications of the Inactivation of Antibiotics and Other Antimicrobial Agents

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