A Molecular basis for human hypersensitivity of aminoglyscoside antibiotics (original) (raw)

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1

Pharmaceutical Sciences, University of Southern Califonia

Los Angeles, CA 90033, USA

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2

Department of Otolaryngology, School of Medicine Akita University

Akita, Japan

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3

Department of Peidatrics, Cedars-Sinai Medical Center

Los Angeles, CA 90048

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4

Department of Amthropology, Pennsylvania State University

PA 16802 USA

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5

Department of Pediatrics, National University of Singapore

Japan

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Gallaudet University

Washington, DC 20002, USA

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* To whom correspondence should be addressed

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Revision received:

16 July 1993

Published:

11 September 1993

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Tim Hutchin, lan Haworth, Koichiro Higashi, Nathan Fischel-Ghodsian, Mark Stoneking, N. saha, Cathy Arnos, Gino cortopassi, A Molecular basis for human hypersensitivity of aminoglyscoside antibiotics, Nucleic Acids Research, Volume 21, Issue 18, 11 September 1993, Pages 4174–4179, https://doi.org/10.1093/nar/21.18.4174
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Abstract

We have investigated the distribution of mitochondrial DNA polymorphisms in a rare maternally transmitted genetic trait that causes hypersensitivity to aminoglycoside antibiotics, In the hope that a characterization of Its molecular basis might provide a molecular and cellular understanding of amlnoglycoside-induced deafness (AGD). Here we report that the frequency of a particular mitochondrial DNA polymorphism, 1555 ° , Is associated nonrandomly with aminoglycoslde-lnduced deafness in two Japanese pedigrees, bringing the frequency of this polymorphism to 5 occurrences In 5 pedigrees of AGD, and in 4 of 78 sporadic cases In which deafness was thought to be the result of aminoglycoside exposure; both frequencies are significantly different from the occurrence of this mutation In the hearing population, which was 0 In 414 individuals surveyed. The 1555 G polymorphism occurred In none of 34 amlnoglycoslderesistant Individuals. We propose a specific molecular mechanism for aminoglycoside hypersensitivity in individuals carrying the 1555 G polymorphism, based on the three-dimensional structure of the rlbosome, in which the 1555 ° polymorphism favors aminoglycoside binding sterically, by increasing access to the therlbosome cleft.

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