The structure of aminoglycoside antibiotic 66-40G produced by Micromonospora inyoensis.

Aminoglycoside antibiotic 66-40G is a minor component produced in the fermentation of Micromonospora inyoensis. Its structure has been established as 3''-de-N-methyl-sisomicin (4) by spectroscopic means and by direct comparison with an authentic sample obtained from photochemical oxidative de-N-methylation of sisomicin (1).

Chemical modification of some gentamicins and sisomicin at the 3''-position.

Chemical and photochemical oxidative methods of de-N-methylation of some gentamicins and sisomicins at the 3''-position are described. Selective acetylation of gentamicins and sisomicins at the 1, 3, 2' and 6' and of gentamicin B at the 1, 3, and 6'positions are achieved by treatment of the free bases with carbon dioxide prior to acetylation. De-N-methylation of the above selectively blocked gentamicins and sisomicins followed by re-alkylation at the 3''-position and de-N-protection gives a series of 3''-N-alkyl analogues. The in vitro antibacterial properties of the new derivatives of gentamicins and sisomicins are given.

Mutational biosynthesis by idiotrophs of Micromonospora purpurea. II. Conversion of non-amino containing cyclitols to aminoglycoside antibiotics.

A mutant of Micromonospora purpurea, which produces the gentamicin complex only when 2-deoxystreptamine is added to the fermentation medium, produces a new antibiotic complex, 2-hydroxygentamicin, when streptamine or 2,4,6/3,5-pentahydroxycyclohexanone is added to the fermentation medium. This mutant also produces the gentamicin complex when 2,4/3,5-tetrahydroxycyclohexanone is added to the fermentation medium. The C1 and C2 components of 2-hydroxygentamicin have broad spectrum in vitro antibacterial activity similar to the gentamicin C1 and C2 components, but with greater activity against some gentamicin-resistant strains.

Mutational biosynthesis by idiotrophs of Micromonospora purpurea. I. Conversion of aminocyclitols to new aminoglycoside antibiotics.

By mutation and strain improvement techniques idiotrophs of Micromonospora purpurea, the gentamicin-producing organism, were obtained which require an exogenous source of 2-deoxystreptamine in order to produce gentamicin. Streptamine incorporation afforded a mixture of 2-hydroxygentamicin C as a complex of essentially the C1 and C2 components whereas 2-deoxystreptamine when incorporated by the same idiotroph afforded the same mixture of C1, C2 and C1a gentamicins as the parent (m1) organism. The 2-hydroxygentamicin C complex exhibited broad-spectrum antibiotic activity with an in vitro potency less than that for the gentamicin C complex, but with greater activity against selected gentamicin C resistant organisms. The LD 50 (i.v.) in mice of the 2-hydroxygentamicin C complex indicated that it had approximately half the toxicity of the gentamicin C complex. 2, 5-Dideoxystreptamine affordeda C1, C2, and C1a mixture of 5-deoxygentamicins, which also had broad spectrum activity, and exhibited improved activity against several gentamicin-acetylating strains of resistant bacteria. The LD50 (i.v.) in mice of the 5-deoxygentamicin C complex indicated that it was about 2.5 times more toxic than the gentamicin C complex. Two derivatives of 2,5-dideoxystreptamine afforded the same mixture of 5-deoxygentamicins. 2-Epistreptamine upon supplementation to a broth containing growing cultures of these idiotrophs also produced antibiotic.

Gentamicins.

Gentamicin is a new broad-spectrum antibiotic, basic and water-soluble, produced and developed by Schering Corporation-Bloomfield, New Jersey (1967 and 1968). It is produced by Micromonospora purpurea, a member of a genus of microorganisms from which no other antibiotics have been derived. Paper chromatographic techniques showed the components of gentamicin complex designated as C', C'a, and C2. Gentamicins are bactericidal antibiotics, active in vivo in low concentrations against a wide spectrum of both Gram-positive and Gram-negative organisms. Among the responsive Gram-positive groups of microorganisms are Staphylococcus aureus including many resistant penicillinase producing strains and group A betahemolytic Streptococci. Among the clinically more important species of Gram-positive organisms responsive to gentamicin are both indole-positive and indole-negative Proteus, Pseudomonas, Escherichia coli, Aerobacter, Klebsiella, Salmonella, and Shigella. The production of gentamicins was improved by adding cobalt to the growth medium.

Selective N-actylation of gentamicin antibiotics-synthesis of 1-N-acyl derivatives.

Treatment of acid addition salts of aminoglycoside-aminocyclitol antibiotics of the gentamicin-sisomicin class, with one equivalent of triethylamine and an acylating agent results in selective formation of 1-N-acyl derivatives. This is in contrast to acylation of the antibiotic free bases which results in preferential acylation of other basic centres in the molecule. Origins of the observed selectivity are discussed. In vitro antibacterial activities of several new 1-N-acy1 derivatives of gentamicin, sisomicin and verdamicin are reported.

Biotransformation, a new approach to aminoglycoside biosynthesis: II. Gentamicin.

Utilizing a paromamine-producing mutant of Micromonospora purpurea blocked in the production of gentamicin, bioconversion of various minor gentamicin components into the gentamicin C complex was demonstrated. The compounds tested were structurally related to the gentamicin C's and are found as minor components in the gentamicin fermentation. Based upon the bioconversions detected, a branched pathway for the biosynthesis of the gentamicin C components is proposed.

Nodular subcutaneous fat necrosis. A manifestation of silent pancreatitis.

A 57-year-old man with asymptomatic pancreatitis developed tender subcutaneous nodules with fat necrosis. These nodules were the sole clinical manifestation of the underlying disease. This case demonstrates that silent pancreatitis should be considered in the differential diagnosis of painful leg nodules.

Gentamicin and gentamicin C1 in the treatment of complicated urinary tract infections: comparative study of efficacy, tolerance, and pharmacokinetics.

The clinical efficacy, patient tolerance, and pharmacokinetics of gentamicin and the single component gentamicin C(1) were studied after single and multiple doses in elderly male patients. Patient tolerance was extremely good at the dose levels used. There was some evidence of renal function impairment due to repeated intramuscular doses of gentamicin, but not gentamicin C(1). The antibiotics were equally effective against the organisms present in the urine of these patients. The pharmacokinetics of the two antibiotic forms were similar, although gentamicin C(1) appeared to have a larger distribution space.