Bacterial resistance to aminoglycoside antibiotics

Bacterial resistance to aminoglycoside antibiotics

R E V I E W S Bacterial resistance to amlnoglycos de antlbmUcs Julian Davies and Gerard D. Wright he aminoglycosides conbacterial membrane damage apT...

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Bacterial resistance to amlnoglycos de antlbmUcs Julian Davies and Gerard D. Wright he aminoglycosides conbacterial membrane damage apThe aminoglycoside antibiotics are stitute a large group of broad-spectrum antibacterial compounds pears to be essentiaP. The [3biologically active bac- that are used extensively for the treatment lactam antibiotics are currently terial secondary metabolites the most prescribed anti-infecof many bacterial infections. In view of (Table 1, Fig. 1). Although they tive agents, but aminoglycothe current concerns over the global rise are best known as antibiotics in antibiotic-resistant microorganisms, side antibiotics are still used for the treatment of a variety of extensively in the treatment of there has been renewed interest in the diseases, such as tuberculosis serious bacterial infections, and mechanisms of resistance to the and serious nosocomial infec- aminoglycosides, including the superfamily combination therapy is often tions, the aminoglycosides have of aminoglycoside-modifying enzymes. recommended, especially in ennumerous applications, a few terococcal infections. The toxJ. Davies* is in the Dept of Microbiology and of which are listed in Table 2. icity of aminoglycosides remains Immunology, University of British Columbia, Here, we will concentrate on a problem; systematic structureVancouver, British Columbia, Canada V6T 1Z3; the aminoglycoside antibiotics, toxicity analyses, providing inG.D. Wright is in the Dept of BiochemistD,, all of which have the ribosome formation that could lead to the McMaster University, Hamilton, Ontario, Canada L8N 3Z5. *tel: +1 604 822 2501, as the primary target; members design of more-effective therafax: +I 604 822 6041, e-mail: [email protected] of this class have a wide variety peutic agents, have not been of biological activities extendcarried out. ing to the modulation of the activity of enzymes and As with all antibiotics, the increasing use of the ribozymes. Aminoglycoside inhibition of bacterial aminoglycosides in the 1960s and 1970s has led to the cell growth occurs by inhibition of one or more of the appearance of resistant bacteria, for example M y c o biochemical steps involved in translation on the ribobacterium tuberculosis strains that are resistant to some 1. This mechanism of action has been confirmed streptomycin, which was the front-line drug for tubercuby the demonstration that point mutations or enzymic losis treatment at the time. All streptomycin-resistant modifications in ribosomal components that reduce M. tuberculosis strains carry point mutations leading aminoglycoside binding to the ribosome confer high- to alterations in the target of the antibiotic action, the level resistance in bacteria. A significant advance in the ribosome. Molecular studies have identified changes in understanding of the aminoglycoside-ribosome interrRNA (Ref. 4) and ribosomal proteins s of the 30S riboaction has been the determination of the 3-D structure somal subunit. The first reports of pathogenic Enteroof the complex between paromomycin and the A site bacteriaceae that were resistant to streptomycin apof 16S ribosomal RNA (Ref. 2). The question of how peared in 1956 in Japan (Ref. 6), and in 1963-1964 aminoglycosides exert their bactericidal effect is more resistance to kanamycin and neomycin emerged worldcontroversial. The process, which is likely to be physio- wide as a result of a genetically transferable mechalogically and biochemically complex, has not yet nism 7. Resistance to the gentamicin-type antibiotics been explained satisfactorily, although some aspect of (3'-deoxy compounds) was reported in 1967 and was also shown to be associated with the presence of R plasmids 8-1°. Unlike the penicillin-inactivating enzymes, where antibiotic hydrolysis is the mechanism of action, Table 1. Aminoglycoside antibiotics transferable resistance to aminoglycosides involves enand their source organism zymes that catalyse cofactor-dependent drug modification of hydroxy or amino groups on the aminocyclitol Aminoglycoside Source organism residuesH, ~z. Kanamycin Streptomyces kanamyceticus Streptomycin Streptomyces griseus Aminoglycoside-modifying enzymes Gentamicin Micromonospora purpurea The three routes to enzymic aminoglycoside inactiSpectinomycin Streptomyces spectabilis vation, ATP-dependent O-phosphorylation by phosButirosin Bacillus circulans photransferases (APH), ATP-dependent O-adenylation Tobramycin Streptomyces tenebrarius by nucleotidyltransferases (ANT) and acetyl CoANeomycin Streptomyces fradiae dependent N-acetylation by acetyltransferases (AAC) Amikacin Semisynthetic derivative of kanamycin (Table 3), have been found in most Gram-negative and Netilmicin Semisynthetic derivative of sisomicin Gram-positive bacterial pathogens 13. Over 50 differIsepamicin Semisynthetic derivative of gentamicin B ent enzymes have been identified as aminoglycoside

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modifiers, including one fusion of an N-acetyltransferase and O-phosphotransferase that is widely distributed in staphylococci and enterococci. This combination protects strains effectively against all available aminoglycosides except streptomycin and spectinomycin. The somewhat confusing nomenclature describing these enzymes has recently been simplified by Shaw et al. 13, who propose a uniform terminology where the predicted regiospecificity of group transfer is delineated by a number in parentheses, and the subfamily, based on the aminoglycoside-resistance profile, is designated by a roman numeral and followed by a letter indicating a specific gene. Thus, APH(3')-Ia is an aminoglycoside kinase that transfers a phosphate to the 3"-hydroxyl of many aminoglycosides, while APH(3')-VIb transfers a phosphate to the same site on aminoglycosides but exhibits a different substrate range and resistance spectrum. Despite the many aminoglycoside enzymes known, detailed studies of their catalytic mechanisms are limited. In most cases, purified enzymes display K m values in the low to sub iteMlevel. In contrast, turnover numbers (kca t o r Vma x )tend to vary significantly and are generally in the order of 0.1-100 s-L This results in specificity constants (kcato r K m) o f - 106-108 M-is -1, confirming that these are highly effective enzymes 14-~6.In cases where

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reliable measurements of steady-state rates have been made, it has generally been observed that the minimum inhibitory concentration is positively correlated with Vmax/Km,the rate at low (sub-Km) aminoglycoside concentrations~4,17,18. This observation makes good biological sense, as it appears that the enzymes have evolved to detoxify low concentrations of aminoglycosides at optimal rates. Structural studies of the aminoglycoside enzymes are, with one exception, limited to interpretations of primary sequence information, although several structural determinations are in progress. Detailed mutational studies are lacking for all classes of enzymes although some reports have proved enlightening. In the case of the aminoglycoside 3'-kinases, Bkizquez et a l ) 9 found Table 2. Therapeutic applications of aminoglycosides Aminogiycoside

Application

Kanamycin, streptomycin, gentamicin Validamycin 1-Deoxynojirimycin, acarbose, allosamidin Paromomycin

Antibacterial antibiotics Antifungal antibiotic Glycohydrolase inhibitors Anthelmintic agent

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Table 3. Arninoglycoside-modifying enzymes a Enzyme

Typical substrates

O-Phosphotransferases(APH) 2' ' - b 3'(-5")3"46-

Kanamycin, gentamicin, tobramycin Kanamyein, neomycin Streptomycin Hygromycin Streptomycin

N-Acetyltransferases (AAC) 12'36 '-b

Apramycin, paromomycin Gentamicin, tobramycin Kanamycin, gentamicin, tobramycin Kanamycin, gentamicin, tobramycin

O-Adenyltransferases(ANT) 2"3" 4"69-

Gentamicin, tobramycin Streptomycin Kanamycin, neomycin Streptomycin Spectinomycin

aFormost enzymesthere are several allozymesthat often differ in substrate range. bA bifunctional enzyme encoded by a gene fusion with both APH(2") and AAC(6') activity has been identified.

that amino acid substitutions introduced into three carboxy-terminal conserved motifs of APH(3")-II reduced substrate activity, as did an alteration near the amino-terminal of the protein. A conserved histidine at position 18 8 was suggested to be a phosphate-accepting residue but has recently been shown not to participate in the catalytic reaction2°. One report of affinity labelling with an ATP analogue demonstrated that Lys44, which is conserved in all APH(3')s, is close to the triphosphatebinding pocket2L However, the exact biochemical functions of the conserved motifs in these enzymes have yet to be confirmed by more-detailed structural studies. In the case of the AAC(6') enzymes, a single point mutation, Leul 19 to Ser, results in the decreased ability to acetylate amikacin, demonstrating that this site plays a role in substrate recognition=; little else is known about binding or catalysis in these enzymes. The crystal structure of one nucleotidyltransferase, ANT(4'), is known and is described in more detail below. Such advanced analyses are sadly lacking for the aminoglycoside enzymes, despite the fact that as much as 30 g of APH(3')-II has been prepared and used for environmental safety studies 23. Genetics

The aminoglycoside-modifying enzymes are encoded by a large group of genes, most of which are unrelated at the nucleotide sequence level and are ostensibly derived from a variety of different microbial origins 13. There is a large reservoir of aminoglycoside-modifying genes in the aminoglycoside-producing bacteria, not only in Streptomyces spp. but also in Micromonospora spp. and even Bacillus spp.

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In the case of bacterial pathogens, aminoglycoside resistance is, with a few exceptions, encoded on extrachromosomal elements such as bacterial plasmids and transposons, which explains the rapid dissemination of resistance within the bacterial population. Of particular significance is the demonstration that the gene for APH(3')-III was transferred from streptococci (enterococci) to Gram-negative Campylobacter spp. in clinical situations; this has been confirmed in the laboratory 24. The aph(3 ) genes from the two sources possess virtually identical nucleic acid sequences. This dispels notions that there are barriers to gene transfer between the unrelated Gram-positive and Gram-negative families of bacteria. It also establishes the concept of genetic flow from Gram-positive to Gram-negative bacteria, which is important when considering the possible origin of aminoglycoside-resistance genes. In addition, aminoglycoside genes have been found on conjugative and non-conjugative plasmids of a variety of incompatibility types and are associated with different transposons. There are no specific genetic associations between the genes involved in aminoglycoside resistance and other antibiotic resistance; the R plasmids found in many isolates of Klebsiella pneumoniae and Staphylococcus aureus carry a variety of different antibiotic-resistance genes, and broad-spectrum aminoglycoside-resistanceharbouring plasmids encoding as many as three different aminoglycoside-modifying enzymes are not uncommon. However, in hospital isolates of methicillinresistant S. aureus (MRSA), the pbp2A gene is almost always associated with aminoglycoside resistance; this probably results from constant antibiotic selection pressure rather than any specific recombination process. In several cases, the genes for aminoglycosidemodifying enzymes are found on the chromosome. For example, Providencia stuartii, a nosocomial pathogen, is less susceptible to antibiotics such as kanamycin and amikacin. This results from the presence of the aac(2")-Ia gene in all isolates of P. stuartii, and biochemical and genetic evidence links this gene with a role in peptidoglycan synthesis, in addition to aminoglycoside resistance, although knockout experiments have demonstrated that it is not an essential gene 2s,26. It has been suggested that the aminoglycosides are 'accidental' substrates of the AAC(2")-Ia enzyme 27, but we consider this notion to be somewhat gratuitous. Almost all clinical isolates of Acinetobacter spp. possess a chromosomal aac(6 ) gene. Other aac(6") genes are chromosomally encoded 28, the aac(6)-Ic gene is found in all Serratia marcescens strains 29 and aac(6)-Ii is common in Enterococcus faecium. Enzymatic analysis of purified, recombinant AAC(6')-Ii suggests that the enzyme has not evolved for optimal aminoglycoside resistance and may have another role in cell function (G.D. Wright and P. Ladak, submitted). It is noteworthy that aminoglycoside-modifying enzymes appear to be common in streptomycetes and mycobacteria and are also chromosomally encoded. Surveys of the expression levels of a variety of aminoglycoside enzymes in different hosts in the presence

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and absence of antibiotics suggest that most of the aminoglycoside-resistance genes are constitutively expressed, although no detailed studies of regulation at the level of transcription have been carried out. The exception is the P. stuartii chromosomal aac(2)-Ia gene, which has been shown to be subject to trans-acting regulation 3°. There are several different biochemical mechanisms of aminoglycoside resistance (Box 1). The rRNA methylase enzymes produced in many aminoglycosideproducing actinomycetes confer very high levels of resistance 31. In recombinant Escherichia coli carrying the gentamicin-resistance gene of the gentamicin-producing strain Micromonospora purpurea, resistance is almost to the solubility limit of the drug 32. Surprisingly, the rRNA methylases have subtly different spectra of resistance, depending on the base modified; for example, there are differences in susceptibility between the kanamycin-, gentamicin- or tobramycin-producing strains that are modified on adjacent nucleotides in the rRNA. This may reflect a high degree of specificity in the aminoglycoside receptors within the ribosome structure 2"33.No clinical isolate that is aminoglycosideresistant as the result of an rRNA methylase has, as yet, been identified. This is in marked contrast to the situation with macrolide antibiotics, where rRNA methylation is common among producing organisms and resistant clinical isolates. The most comprehensive phylogeny studies of the aminoglycoside-resistance genes have been presented by Shaw and colleagues 13. These studies confirm the multiple sources of the genes; most do not show greater than 40% similarity at the protein level, the similarities being found within common motifs that apparently identify substrate-binding structures on the enzyme or are critical to protein folding. In a few cases, the aminoglycoside enzymes from different sources are quite similar; one interesting example of relatedness between enzymes from diverse sources is APH(6), where the proteins encoded by the broad-host-range plasmid RSF1010, Mycobacterium fortuitum and streptomycin-producing Streptomyces griseus show almost 60% sequence homology (Fig. 2). The aminoglycoside-modifying enzymes and their substrate antibiotics have been employed as selective markers on cloning vectors for a wide variety of recombinant DNA applications in prokaryotes and eukaryotes. Neomycin, kanamycin, G418 (a member of the gentamicin B family, known as geneticin), apramycin and hygromycin have been used extensively in cloning studies in plant, animal and human cells. The gene for APH(3')-II was one of the first bacterial genes to be expressed in humans during early studies of delivery systems for human gene therapy. Origins of aminoglycoside resistance As there must be a very large number of diverse aminoglycoside-resistance enzymes, unique precursor-related evolutionary pathways for the different enzyme types cannot be constructed. Is there likely to be an 'allinclusive' source? The obvious choice is the organisms that produce antibiotics 34, and there is now good sup-

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Box 1. Mechanisms of resistance to aminoglycoside antibiotics

• • • • °

Reduced uptake Mutational modification Mutational modification Enzymic modification of Enzymic modification of

of 16S rRNA of ribosomal proteins 16S rRNA antibiotics

port for this notion. In the first place, the aminoglycoside-producing microorganisms have mechanisms of aminoglycoside resistance that are formally identical, in a biochemical sense, to those found in clinical isolates and, as mentioned above, there are strong sequence relationships in some cases 3s. There is one exception. The O-adenyltransferases, which modify and determine resistance to the streptomycin/spectinomycin, neomycin and gentamicin/kanamycin classes of aminoglycosides, have few congeners in any other species of bacteria. A streptomycin O-adenylyltransferase has been described in Bacillus subtilis, but little work has been carried out on this determinant and no comparative studies have been done36; apparently, the gene is chromosomal. The recently elucidated crystal structure of ANT(4') does present some interesting possibilities 3v. The overall protein fold of this enzyme is similar to other known enzymes that catalyse nucleosidemonophosphate transfer-generating pyrophosphates such as rat DNA polymerase B (Ref. 38). While the ANTs are the least homogeneous group of aminoglycoside-modifying enzymes, most share the sequence Gly-Ser-(Xaa) 10-12-(Asp,Glu)-Xaa-(Asp,Glu), which forms a portion of the ATP and Mg 2+ binding sites in the ANT(4') crystal structure. It is therefore possible that ANTs may have been co-opted from existing metabolic enzymes, such as DNA polymerases. This hypothesis awaits further elucidation of ANT 3-D structures. O-phosphotransferases and N-acetyltransferases are common to producing strains, as both self-resistance and biosynthetic enzymes. Comparative studies have been made at the gene and protein level and, in a few cases, the sequence similarities are strong. Piepersberg has carried out extensive phylogenetic analyses and proposes that the aminoglycoside phosphotransferases are related to protein kinases (not sugar kinases as might be predicted) and the aminoglycoside acetyltransferases are similar to protein acylases 39. Only limited studies have been carried out with the purified enzymes, and kinetic analyses of the enzymes isolated from producing strains have not been done, although recent mechanistic work with APH(3')-III supports the protein kinase link 2°. As an approach to comparing protein structure, we have analysed the antibody crossreactivity of the APH(3') proteins (G.D. Wright and J. Davies, unpublished). This group shows significant primary sequence similarity and impressive antigenic crossreactivity, thus demonstrating the close physical relationship within this group of enzymes; despite their differences in substrate specificity and ability to confer resistance to aminoglycosides, they are closely related in a 3-D sense.

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This further emphasizes the need for X-ray or N M R structure analyses, and the results of current studies on APH(3")-IIIa, which will provide a solid basis for molecular analyses, are awaited eagerly. One of the strongest pieces of evidence for natural gene transfer between antibiotic-producing streptomycetes and other bacteria has come from a study of human infections in which mixed cultures of Streptomyces spp. and Mycobacterium spp. were found to possess common genes for resistance to tetracycline 4°. Both species carried two identical classes of tetracyclineresistance determinants. Fast-growing mycobacteria carry genes for APH(6) (see Fig. 2) and for AAC(3") (Ref. 41), but until nucleotide sequence analysis has been completed on the latter, the relationship to other aminoglycoside enzymes remains unclear. Martin and

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co-workers discovered an aac2"gene in M. fortuitum; nucleotide sequence analysis shows that the gene and derived protein sequence are somewhat related to the P. stuartii aac2" gene 42. At the protein sequence level there is 38% identity and 63% similarity. Other mycobacteria (including M. tuberculosis) carry the same chromosomal gene (C. Martin, pers. commun.). As mycobacteria and streptomycetes are both common inhabitants of soil, inheritance of an aminoglycoside enzyme from a microbial source such as streptomycetes may involve a cascade of multiple transfers between related species in bacterial populations of considerable diversity, probably involving mycobacteria. Thus, every aminoglycoside-resistance determinant may have evolved by multiple transfers that have pursued independent routes involving different hosts.

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The acquisition of resistance genes from source bacteria can be accomplished in the form of gene cassettes, which are open reading frames (ORFs) that encode an antibiotic-resistance gene (for example, an aminoglycoside-modifying enzyme). The gene cassettes, in circular form, are inserted by a site-specific process into a naturally occurring gene-expression element containing the transcription and translation signals required for expression of the ORF in a wide variety of bacteria. This mechanistic concept, termed the integron proc e s s 43'44, has been well established in Gram-negative bacteria. However, if the aminoglycoside-resistance genes originated and evolved in Gram-positive bacteria and were then transformed to Gram-negative bacteria as described above, an appropriate acquisition process for resistance determinants in Gram-positive bacteria has to be found. This remains a mystery, although it is intriguing to note that an ancestral transposon related to Gram-negative integrons has been identified in mycobacteria 4s. It has been suggested that streptomycete DNA found as contamination in antibiotic preparations could have played a role in the development (acquisition) of antibiotic-resistance genes 46. With respect to dissemination of aminoglycoside resistance within the bacterial population, no single mechanism of gene transfer has been identified, and it is assumed that the processes of conjugation, transformation and even transduction are equally probable within mixed bacterial populations. Finally, there is a striking correspondence between the appearance of certain types of aminoglycosideresistance mechanisms and aminoglycoside use. The Schering Plough group has analysed the distribution of aminoglycoside enzymes in different countries in response to different aminoglycoside-antibiotic treatment regimes 47. The most common aminoglycosideresistance enzymes in Gram-negative pathogens are AAC(6')s; their distribution correlates with the use of antibiotics related to the kanamycin/amikacin group (as opposed to the gentamicin group) and demonstrates the roles of the selective pressures of antibiotic usage in the worldwide rise in aminoglycoside resistance. While the heyday of therapeutic use of the aminoglycoside antibiotics may have passed, a substantial number of medical, biochemical, microbiological and evolutionary problems related to the use of the aminoglycoside antibiotics (and indeed any antimicrobial agent in the future) remain to be solved. Encounters with the microbial world are close but complex! Acknowledgements

We thank the followingfor their support: the CanadianBacterialDiseasesNetwork (J.D.),the NationalScienceand EngineeringCouncilof Canada (J.D.) and the MedicalResearchCouncilof Canada(G.D.W.). References

1 Cundliffe,E. (1981) in The Molecular Basis of Antibiotic Action (Gale, E.F.et al., eds), pp. 401-457, John Wiley& Sons 2 Fourmy,D. etal. (1996) Science 274, 1367-1371 3 Davis,B.D. (1988)J. Antimicrob. Chemother. 22, 1-3 4 Meier,A. et al. {1994)Antimicrob. Agents Chemotber. 38, 228-233

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Questions for future research

• What relationships will 3-D structures reveal within the aminoglycoside enzymes? • Did the aminoglycoside phosphotransferases evolve from protein kinases? • What is the origin of the O-adenyltransferases? • Will it be possible to design useful inhibitors of aminoglycoside enzymes that can be used in combination with aminoglycosides to kill aminoglycoside-resistant strains? Will this increase aminoglycoside use? • What are the roles of chromosomally encoded aminoglycosidemodifying enzymes?

5 HonorS,N. and Cole,S.T. (1994)Antimicrob.Agents Cbemother. 38,238-242

6 Umezawa,H. etal. (1967) Science 157, 1559-1561 7 Lehek,G. (1963) Zentralbl. Bakteriol. Parasitenk. 188, 494-505 8 Benveniste,R. and Davies,J. (1971) FEBS Lett. 14, 293-296 9 Martin,C.M. et al. (1971)J. Infect. Dis. 124, 824 10 Witchitz,J.L. and Chabbert,Y.A. (1971),I. Antibiot. 24, 137-141 11 Okamoto,S. and Suzuki,Y. (1965) Nature 208, 1301-1303 12 Benveniste,R. and Davies,J. (1973) Annu. Rev. Biocbem. 42, 471-506 13 Shaw,K.J.et al. (1993) Microbiol. Rev. 57, 138-163 14 McKay,G.A.,Thompson,P.R. and Wright,G.D. (1994) Biochemistry 33, 6936-6944 15 Siregar,J,J., Lerner,S.A.and Mobashery,S. (1994)Antimicrob. Agents Cbemotber. 38, 641-647 16 Siregar,J.J., Miroshnikov,K. and Mobashery,S. (1995) Biochemistry 34, 12681-12688 17 Davies,J. and Smith,D.I. (1978) Annu. Rev. M~crobiol. 32, 469-518 18 Radika,K. and Northrop, D.B. (1984) Antimicrob. Agents Cbemother. 25,479-482 19 Bl~.zquez,J. et al. (1995) Antimicrob. Agents Cbemother. 39, 145-149 20 Thompson,P.R., Hughes,D.W. and Wright,G.D. (1997) Chem. Biol. 3,747-755 21 McKay,G.A.et al. (1994) Biochemistry 33, 14115-14120 22 Rather,P.N. et al. (1992)J. Bacteriol. 174, 3196-3203 23 Fuchs,R.L.et al. (1993) Biotechnology 11, 1537-1542 24 Brisson-Noi~l,A., Arthur, M. and Courvalin,P. (1988) J. Bacteriol. 170, 1739-1745 25 Rather,P.N. et al. (1993)J. Bacteriol. 175, 6492-6498 26 Payie,K.G.,Rather,P.N. and Clarke,A.J. (1995)J. Bacteriol. 177, 4303-4310 27 Macinga,D.R., Parojcic,M.M. and Rather,P.N. (1995) J. Bacteriol. 177, 3407-3413 28 Ploy,M-C. et al. {1994)Antimicrob.Agents Chemother. 38, 2925-2928 29 Shaw,K.J. et al. (1992) Antimicrob. Agents Cbernother. 36, 1447-1455 30 Macinga,D.R. and Rather,P.N. (1996) Mol. Microbiol. 19, 511-520 31 Cundliffe,E. (1989) Annu. Rev. Microbiol. 43, 207-233 32 Holmes,D.J. and Cundliffe,E. (1991) Mol. Gen. Genet. 229, 229-237 33 Hotta, K. et al. (1996)J. Antibiot. 49, 682-688 34 Benveniste,R. and Davies,J. (1973) Proc. Natl. Acad. Sci. U. S. A. 70, 2276-2280 35 Davies,J. in Antibiotic Resistance: Origins, Evolution, Selection and Spread (CibaFoundationSymposium207), John Wiley& Sons (in press) 36 Kono,M. et al. (1987) FEMS Microbiol. Lett. 40, 223-228

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Beyond vancomycin: new therapies to meet the challenge of glycopeptide resistance Thalia I. Nicas, Michael L. Zeckel and Daniel K. Braun ram-positive bacteria are The incidence of infections caused by and teicoplanin will continue, a major cause of infecresistant Gram-positive pathogens is or even increase, in the near tious diseases world- increasing, while emergence of vancomycin future. wide. With the widespread use resistance is reducing the number of The emergence of glycoof antimicrobials and other en- therapeutic options. New agents are being peptide resistance has focused vironmental pressures, the inrapidly evaluated as candidates to replace attention on the need for altercidence of infections caused vancomycin; some of the most promising natives to vancomycin. Vancoby antibiotic-resistant Graminclude semisynthetic glycopeptides, mycin-resistant Enterococcus positive bacteria has rapidly quinupristin-dalfopristin, oxazolidinones faecium (VRE) has become a increased in recent years, espe- and everninomycins. Alternative strategies, major infectious diseases probcially among nosocomial inlem in many hospitals in the including immunization and therapeutic fections. Vancomycin has been vaccines, may also have a role. USA, especially among debilia potent antibiotic against tated and immunocompromised T.I. Nicas*, M.L. Zeckel and D.K. Braun are in the multiresistant Gram-positive hosts ~,2. A Centers for Disease Lilly Research Laboratories, Eli Lilly and Company, bacteria for many years and, Control and Prevention (CDC) Indianapolis, IN 46285, USA. until recently, all major Gramstudy in the USA showed that *tel: +1 317 276 4236, fax: +1 ,317 277 0778, positive pathogens have been overall frequency of vancoe-mail: [email protected] uniformly susceptible. Use of mycin resistance in enterococci vancomycin in developed countries has increased over rose from <0.03% in 1988 to 7.9% in 1993, with 13.8% the past decade in response to the emergence and in intensive care units 3. This trend is continuing. Conspread of highly antibiotic-resistant microorganisms, cerns over glycopeptide resistance are not restricted especially methicillin-resistant Staphylococcus aureus to the enterococci; teicoplanin-resistant coagulase(MRSA) and methicillin-resistant Staphylococcus negative staphylococci are well-documented and epidermidis (MRSE). In the USA, vancomycin is the there are increasing numbers of reports of coagulaseonly antibiotic approved for use against MRSA, negative staphylococci with intermediate or greater whereas in Europe, teicoplanin, a compound of the resistance to vancomycin 4-s. Species include both same chemical class (the glycopeptide antibiotics), is Staphylococcus haemolyticus and S. epiderrnidis. available. Although vancomycin resistance has not yet been reFor treatment of life-threatening infections, such as ported among clinical isolates of S. aureus, vancomycinendocarditis or sepsis caused by MRSA, and serious in- resistant S. aureus has been obtained in vitro 9 by plasfections caused by MRSE and other methicillin-resistant mid transfer from enterococci. Many scientists and coagulase-negative staphylococci, especially those inphysicians fear that it is only a matter of time before volving prosthetic devices, vancomycin is still a powvancomycin-resistant Staphylococcus aureus appears erful weapon. The increasing frequency with which in patients. Natural and laboratory transfer to other MRSA, MRSE and related bacteria are encountered in genera has been reported 1°,1~, and recent reports 12a3 hospitals makes it likely that high usage of vancomycin of isolates of Streptococcus mitis and Streptococcus

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