The crisis in antibiotic resistance has resulted in an increasing fear of the emergence of untreatable organisms. Resistance to the glycopeptide antibiotic vancomycin in the enterococci, and the spread of these pathogens throughout the environment, has shown that this scenario is a matter of fact rather than fiction. Enterococci are frequent causes of nosocomial infections and are intrinsically resistant to many antibiotics, being susceptible only to synergistic penicillin͞aminoglycoside therapy or to the glycopeptide antibiotic vancomycin (1). The recent emergence of resistance to vancomycin in these organisms (2, 3) has been greeted with grave alarm, not only because of the immediate problem of how to treat an infection when no other good drugs are available, but also because vancomycin-resistant enterococci (VRE) may serve as a reservoir for Van R genes, which will no doubt eventually make their way into more virulent organisms such as those of the genus Staphylococcus. Highlevel resistance to vancomycin in VRE (minimal inhibitory concentration Ͼ 1,000 g͞ml) is conferred by five genes located on a transposable element (4). These genes include vanR and vanS, which encode a two-component regulatory system that directs the transcription of three structural genes: The origin of the Van R genes has been the subject of some speculation. Related to this question is the increasing debate concerning the prudence of the continued agricultural use of glycopeptide antibiotics such as avoparcin (8-12) in view of the capacity for selection of VRE in the environment (13-15). That environmental VRE isolates have not been observed yet in North America where glycopeptides are not used in agriculture (16), unlike the situation in Europe, adds another dimension to the debate.The amino acid sequence of the vancomycin-resistance enzyme VanA (17) and the related VanB (18) shows between 20% and 35% sequence homology to other Ddls, including the D-Ala-D-Lac ligases from organisms that are intrinsically resistant to vancomycin such as Leuconostoc spp. and Lactobacillus spp. (19). As part of an ongoing study of the biosynthesis of glycopeptide antibiotics, we have cloned the complete ddl gene from the glycopeptide-producing organism Streptomyces toyocaensis NRRL 15009, which produces the aglycopeptide A47934, and a partial ddl gene from Amycolatopsis orientalis, which produces vancomycin (Fig. 1). These genes encode proteins that show a high degree of homology to the VanA and VanB ligases and suggest that clinical vancomycin resistance may have originated in glycopeptide-producing organisms.
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