The syntheses and biological properties of 1-N-(S-4-amino-2-hydroxybutyryl)-gentamicin B and 1-N-(S-3-amino-2-hydroxypropionyl)-gentamicin B.

Sch 21420 is a new aminoglycoside synthesized from gentamicin B. Susceptibility tests with Sch 21420, amikacin, gentamicin, netilmicin, sisomicin, and tobramycin were performed on a variety of bacterial species including 44 with known mechanisms of resistance to aminoglycosides. Sch 21420 and amikacin had similar effects on all except Haemophilus influenzae and Neisseria species, which were more susceptible to amikacin. Except with some strains of Serratia marcescens, the drugs used were bactericidal. Sch 21420 and amikacin were more stable than the other four aminoglycosides in the presence of the inactivating enzymes produced by some strains. Strains which were very resistant to Sch 21420 and amikacin either were permeability mutants or produced AAC (6')-I inactivating enzyme. The effect of cations on the susceptibilities of these strains to Sch 21420 and amikacin was seen mostly with Pseudomonas aeruginosa and to Sch 21420 with Acinetobacter. Cations did not affect the susceptibilities of other Pseudomonas species, Enterobacteriaceae, Staphylococcus aureus, or Streptococcus faecalis to Sch 21420 or amikacin.Sch 21420 is an aminoglycoside which was synthesized by a method similar to that used in the synthesis of amikacin, except that gentamicin B was used in place of kanamycin (12). The activity ofthis compound was found to be similar to that of amikacin against the Enterobacteriaceae and Pseudomonas aeruginosa (7,9,11,13,15,17).In this study, we compared the inhibitory and bactericidal activities of Sch 21420 to those of amikacin, gentamicin, netilmicin, sisomicin, and tobramycin against a wide variety of gram-positive and gram-negative organisms. The effect of differences in inoculum size and cation concentration on the activity of these six aminoglycosides was assessed. The activities of these drugs on organisms with various mechanisms of resistance (inactivating enzymes and permeability mutants) were also compared.

Section: Resultsmentioning

confidence: 99%

“…Sch 21420 is an aminoglycoside which was synthesized by a method similar to that used in the synthesis of amikacin, except that gentamicin B was used in place of kanamycin (12). The activity ofthis compound was found to be similar to that of amikacin against the Enterobacteriaceae and Pseudomonas aeruginosa (7,9,11,13,15,17).…”

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confidence: 99%

Comparison of in vitro activity of Sch 21420, a gentamicin B derivative, with those of amikacin, gentamicin, netilmicin, sisomicin, and tobramycin

Thornsberry¹,

Barry²,

Jones³

et al. 1980

“…While most aminoglycosides routinely lose their potency due to inactivation by an aminoglycoside-modifying enzyme, butirosin is able to elude many inactivating enzymes, thus retaining its bactericidal capabilities (51). This observation prompted the development of semisynthetic N1-substituted aminoglycoside antibiotics such as amikacin and arbekacin (kanamycin A and dibekacin derivated at N1 by AHB, respectively) (23,26,30,31), isepamicin (gentamicin B substituted with 4-amino-2-hydroxypropionyl at N1) (41), and netilmicin (sisomicin with an ethyl group introduced at N1) (54). These compounds have been shown to be clinically useful against some aminoglycoside-resistant strains, such as methicillin-resistant Staphylococcus aureus (29).…”

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confidence: 99%

Structural Basis of APH(3′)-IIIa-Mediated Resistance to N1-Substituted Aminoglycoside Antibiotics

Fong

Berghuis

2009

Butirosin is unique among the naturally occurring aminoglycosides, having a substituted amino group at position 1 (N1) of the 2-deoxystreptamine ring with an (S)-4-amino-2-hydroxybutyrate (AHB) group. While bacterial resistance to aminoglycosides can be ascribed chiefly to drug inactivation by plasmid-encoded aminoglycoside-modifying enzymes, the presence of an AHB group protects the aminoglycoside from binding to many resistance enzymes, and hence, the antibiotic retains its bactericidal properties. Consequently, several semisynthetic N1-substituted aminoglycosides, such as amikacin, isepamicin, and netilmicin, were developed.

“…Sch 21420 is a semisynthetic aminoglycoside which is produced from gentamicin B by a process similar to that used to produce amikacin from kanamycin A (9). The in vitro activity of Sch 21420 is similar to that of amikacin (2, 11-13, 16), but Sch 21420 has the potential for diminished nephrotoxicity (6).…”

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confidence: 99%

Interpretive standards for disk susceptibility tests with Sch 21420 and amikacin

Barry¹,

Thornsberry²,

Jones³

et al. 1980

Disk susceptibility tests with two structurally related aminoglycosides (amikacin and Sch 21420) were evaluated. Tests with 10-and 30-,ug amikacin disks confirmed previous recommendations for interpretive zone standards; 30-,ug disks are preferred. Tests with 10-, 20-, and 30-,ug Sch 21420 disks led to similar conclusions. The 30-,ug Sch 21420 disks are recommended, with zone standards of c14 mm for the resistant category (minimal inhibitory concentration, 232 ,Lg/ml) and 217 mm for the susceptible category (miniimal inhibitory concentration, -16