In vivo analysis of structure-activity relationships among four aminoglycosides

Gentamicin, netilmicin, 1-N HAPA gentamicin B and amikacin

Richard V. Goering, C. C. Sanders, W. E. Sanders

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Abstract

Structure-activity relationships for gentamicin, netilmicin, amikacin, and 1-N HAPA gentamicin B were compared in treatment of mice lethally infected with a variety of Enterobacteriaceae. The relative activity of the antibiotics against non-enzyme producing strains was analyzed as an indicator of intrinsic potency determined primarily by the basic aminoglycoside ring structure. Activity against strains producing two types of aminoglycoside-inactivating enzymes was analyzed on the basis of ring structure modifications affecting susceptibility to enzyme inactivation. Results of protection tests with strains possessing no enzyme activity generally correlated with structure-activity relationships previously determined in vitro. The two 'gentamicin-like' antibiotics, gentamicin and netilmicin, had a greater intrinsic potency than the two 'kanamycin-like' antibiotics, amikacin and 1-N HAPA gentamicin B. In vitro results were less predictive of in vivo potency in tests with strains producing aminoglycoside-inactivating enzymes. Although these latter organisms all initially appeared susceptible to the four antibiotics in vitro, rapid emergence of resistance in vivo was observed in several instances. The therapeutic efficacy against these strains, however, was related to specific aminoglycoside ring structure modifications affecting the susceptibility of the drugs to inactivating enzymes. The 'kanamycin-like' drugs, amikacin and 1-N HAPA gentamicin B, were more active than gentamicin and netilmicin against AAC (2') producing strains while gentamicin alone was most effective against AAC (6') producing strains.

Original languageEnglish
Pages (from-to)329-341
Number of pages13
JournalCurrent Therapeutic Research - Clinical and Experimental
Volume26
Issue number3
StatePublished - 1979

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Netilmicin
Amikacin
Aminoglycosides
Structure-Activity Relationship
Gentamicins
Anti-Bacterial Agents
Enzymes
Kanamycin
aminoglycoside 2'-N-acetyltransferase
Enterobacteriaceae
Pharmaceutical Preparations
isepamicin
gentamicin B
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

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title = "In vivo analysis of structure-activity relationships among four aminoglycosides: Gentamicin, netilmicin, 1-N HAPA gentamicin B and amikacin",
abstract = "Structure-activity relationships for gentamicin, netilmicin, amikacin, and 1-N HAPA gentamicin B were compared in treatment of mice lethally infected with a variety of Enterobacteriaceae. The relative activity of the antibiotics against non-enzyme producing strains was analyzed as an indicator of intrinsic potency determined primarily by the basic aminoglycoside ring structure. Activity against strains producing two types of aminoglycoside-inactivating enzymes was analyzed on the basis of ring structure modifications affecting susceptibility to enzyme inactivation. Results of protection tests with strains possessing no enzyme activity generally correlated with structure-activity relationships previously determined in vitro. The two 'gentamicin-like' antibiotics, gentamicin and netilmicin, had a greater intrinsic potency than the two 'kanamycin-like' antibiotics, amikacin and 1-N HAPA gentamicin B. In vitro results were less predictive of in vivo potency in tests with strains producing aminoglycoside-inactivating enzymes. Although these latter organisms all initially appeared susceptible to the four antibiotics in vitro, rapid emergence of resistance in vivo was observed in several instances. The therapeutic efficacy against these strains, however, was related to specific aminoglycoside ring structure modifications affecting the susceptibility of the drugs to inactivating enzymes. The 'kanamycin-like' drugs, amikacin and 1-N HAPA gentamicin B, were more active than gentamicin and netilmicin against AAC (2') producing strains while gentamicin alone was most effective against AAC (6') producing strains.",
author = "Goering, {Richard V.} and Sanders, {C. C.} and Sanders, {W. E.}",
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T1 - In vivo analysis of structure-activity relationships among four aminoglycosides

T2 - Gentamicin, netilmicin, 1-N HAPA gentamicin B and amikacin

AU - Goering, Richard V.

AU - Sanders, C. C.

AU - Sanders, W. E.

PY - 1979

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N2 - Structure-activity relationships for gentamicin, netilmicin, amikacin, and 1-N HAPA gentamicin B were compared in treatment of mice lethally infected with a variety of Enterobacteriaceae. The relative activity of the antibiotics against non-enzyme producing strains was analyzed as an indicator of intrinsic potency determined primarily by the basic aminoglycoside ring structure. Activity against strains producing two types of aminoglycoside-inactivating enzymes was analyzed on the basis of ring structure modifications affecting susceptibility to enzyme inactivation. Results of protection tests with strains possessing no enzyme activity generally correlated with structure-activity relationships previously determined in vitro. The two 'gentamicin-like' antibiotics, gentamicin and netilmicin, had a greater intrinsic potency than the two 'kanamycin-like' antibiotics, amikacin and 1-N HAPA gentamicin B. In vitro results were less predictive of in vivo potency in tests with strains producing aminoglycoside-inactivating enzymes. Although these latter organisms all initially appeared susceptible to the four antibiotics in vitro, rapid emergence of resistance in vivo was observed in several instances. The therapeutic efficacy against these strains, however, was related to specific aminoglycoside ring structure modifications affecting the susceptibility of the drugs to inactivating enzymes. The 'kanamycin-like' drugs, amikacin and 1-N HAPA gentamicin B, were more active than gentamicin and netilmicin against AAC (2') producing strains while gentamicin alone was most effective against AAC (6') producing strains.

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