Introduction: Solving the Clinical Problem of Vancomycin Resistance

Vancomycin was isolated by scientists at Eli Lilly and Company (Lilly) in the mid-1950s from a soil sample obtained in the interior jungle of Borneo. The organism producing vancomycin was identified as a Streptomyces species (now known as Streptomyces orientalis, subsequently renamedAmycolatopsis orientalis) [1]. Because of the rapid emergence of penicillin resistance in staphylococci, the drug, which has an outstanding spectrum of activity against Gram-positive cocci, including staphylococci, streptococci and enterococci, was rapidly approved by the United States Food and Drug Administration. Nonetheless, it was not widely used by clinicians, because it was perceived to have significant otoand nephrotoxicity. As it turns out, much of this toxicity may have been due to impurities in the original preparations (dubbed ‘‘Mississippi mud’’ because of the brown-black color of the powder) [2]. Methicillin and the other antistaphylococcal penicillins were developed concomitantly and were much more widely used by clinicians, who considered them safer and at least equally efficacious drugs for staphylococcal infections. With the emergence of methicillin resistance in staphylococci, however, vancomycin use began to increase steadily. Interestingly, for the first 35 years after its discovery, the development of resistance among previously susceptible organisms was virtually unknown. However, the emergence of vancomycin resistance in enterococci in the mid-1980s served as a wake-up call, and antibiotic chemists at Lilly began efforts to discover chemical modifications of the basic vancomycin nucleus that would confer activity against vancomycin-resistant organisms [3]. They synthesized numerous derivatives of chloroeremomycin, a close analog of vancomycin, and discovered that the addition of side chains to the vancosamine sugar on the molecule resulted in compounds with activity against vancomycin-resistant enterococci (VRE). A derivative with a chlorobiphenylmethyl group attached to the vancosamine terminal monosaccharide of the disaccharide moiety (oritavancin) showed greatest activity. Originally, the basis for this activity was somewhat puzzling because the modifications were made at a position on the molecule far removed from the putative binding site of vancomycin for D-ala-D-alanine, which enables the antibiotic to inhibit cell wall synthesis in Gram-positive bacteria. A number of theories, including dimerization, which allowed the molecule to bind more tightly to the outer cell envelope of Grampositive bacteria, were put forth, but none provided a definitive explanation for the activity of oritavancin against VRE [4]. Subsequently, Ge et al were able to demonstrate that a portion of the modified chloroeremomycin molecule containing the vancosamine terminal monosaccharide with a chlorobiphenylmethyl side chain actually had activity enabling it to inhibit the second step in Grampositive cell wall synthesis [5]. Later work has demonstrated that oritavancin inhibits transpeptidation in VRE by interfering with the ability of D-aspartate to form a cross-link with the penultimate D-alanine in the growing cell wall [6]. As it turns out, oritavancin, the compound synthesized by Lilly with the greatest activity against Gram-positive organisms, is now known Correspondence: Robert C. Moellering Jr, MD, Department of Medicine, Beth Israel Deaconess Medical Center, 110 Francis St, Ste 6A, Boston, MA 02215 (rmoeller@bidmc.harvard.edu). Clinical Infectious Diseases 2012;54(S3):S201–2 The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. DOI: 10.1093/cid/cir1046