Genes involved in antibiotic resistance vary within a species

December 16, 2008

CLEVELAND - December 16, 2008 - The recent emergence of multidrug resistance (MDR) in Acinetobacter baumannii, a bacteria that causes infections primarily among seriously ill patients in the intensive care unit who may have reduced immune systems, has raised concern in health care settings worldwide. When comparing the genome sequence of three MDR A. baumannii isolates and three drug-susceptible A. baumannii isolates, Case Western Reserve University School of Medicine found that one variation of bacteria would respond to antibiotics while another variation of the same bacteria may not.

A. baumannii is currently recognized by the Infectious Diseases Society of America as one of the most important pathogens threatening our health care delivery system.

Over the last 10-15 years, A. baumannii has become increasingly resistant to antibiotics and now more than one-third of infections are MDR, which means these pathogens are resistant to at least three different classes of antibiotics. This pattern of resistance to many antibiotics limits the ability of physicians to treat serious infections caused by A. baumannii.

The study, led by Mark Adams, Ph.D., Associate Professor in the Department of Genetics at Case Western Reserve University School of Medicine, is titled "Comparative Genome Sequence Analysis of Multidrug-Resistant Acinetobacter baumannii", and is in the December issue of the Journal of Bacteriology.

Adams first sequenced the genome of an MDR isolate and his collaborator in Buffalo, Steven Gill, Ph.D., Associate Professor of Oral Biology at SUNY Buffalo, sequenced two drug susceptible isolates to learn more about the genes (the genome contains the complete set of genes) that control resistance to antibiotics. Adams then compared the new sequence with genomes of other MDR and drug susceptible isolates, comparing six complete genomes.

What they found is that within a hospital or even a person, there can be a variation within the bacteria which means that it can affect how the infection reacts to antibiotics.

"A key conclusion of our study is that even very closely related isolates of A. baumannii can differ significantly in the set of resistance genes that they carry," said Adams. "It is known that resistance genes can be shared between bacteria (horizontal gene transfer), and it appears that this is a frequent event, with genes entering a genome and being deleted even across a single outbreak."

"We used to think--you treat this bacteria with this drug--but now we know that you have to look more carefully not just at the bacteria but at each one's genetic characteristics," said Adams. "This is an argument for targeted therapy in infectious disease because you want to select an antibiotic that will be effective against the particular genetic characteristics of the bug that's causing the infection."

The scientists also found that each isolate has a somewhat different set of genes.

"About three-fourths of the genes are shared by all the isolates, while the remainder are unique to different subsets," said Adams. "We identified 475 genes that are shared by all six clinical isolates of A. baumannii but are not present in a closely related Acinetobacter species that does not cause infections. These genes merit further study to help figure out what makes A. baumannii able to live in association with humans and cause disease."
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This is the first genome sequence to be determined in Cleveland.

Funding was provided by a grant from Steris Foundation to Adams and by funding from the National Institutes of Health to a collaborator in this study, Robert Bonomo, M.D., Associate Professor of Medicine, Pharmacology and Molecular Biology and Microbiology at Case Western Reserve University School of Medicine, and Geriatric Research, Education and Clinical Center and Infectious Diseases at Louis Stokes Cleveland Department of Veteran Affairs Medical Center. Dr. Bonomo published an article in 2006 about an initial outbreak at Walter Reed where a number of soldiers had the same bacteria but it was treated differently based on its genetic variations.

About Case Western Reserve University School of Medicine

Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and 15th largest among the nation's medical schools for research funding from the National Institutes of Health. Eleven Nobel Laureates have been affiliated with the school.

The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching and in 2002, became the third medical school in history to receive a pre-eminent review from the national body responsible for accrediting the nation's academic medical institutions. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century.

Annually, the School of Medicine trains more than 600 M.D. and M.D./Ph.D. students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News and World Report Guide to Graduate Education. The School of Medicine's primary clinical affiliate is University Hospitals and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic Foundation, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. http://casemed.case.edu.

CONTACT:
Jessica Studeny
216.368.4692
Jessica.Studeny@case.edu

Case Western Reserve University

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