Journal of Microbes and Infection, March 2009, Vol. 4, No. 1 ,

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1 Journal of Microbes and Infection, March 2009, Vol. 4, No : 16S rrna,, : 30S 16S rrna A 16S rrna, 4, 6- - ( ), G + C G + C, 16S rrna,, : 16S rrna ; ; A novel aminoglycoside resistance determinant: plasmid-mediated 16S rrna methylase WU Qiong, NI Yu-Xing Department of Clinical Microbiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai , China Abstract: Aminoglycosides have been used for the treatment of a broad range of life-threatening Gram-positive and Gram-negative bacterial infections. These agents bind to the A site of the 16S rrna of the bacterial 30S ribosomal subunit and subsequently block growth through interference with protein synthesis. The mechanisms of resistance to aminoglycosides in pathogenic bacteria were previously believed to be restricted to production of aminoglycosidemodifying enzymes, a decrease in intracellular antibiotic accumulation, and the substitution of ribosomal proteins or mutation of rrna. Plasmid-mediated 16S rrna methylases, which confer a high level of resistance to various clinically important aminoglycosides, including 4, 6-disubstituted deoxystreptamine aminoglycoside, were reported to be involved as part of a novel aminoglycoside resistance mechanism in pathogenic Gram-negative rods. At present, six types of plasmid-mediated 16S rrna methyltransferase genes, arma, rmta, rmtb, rmtc, rmtd, and npma have been found in members of the family Gram-negative bacilli. Also, these genes are mediated by bacterium-specific recombination systems, such as transposons, and are easily translocated to other DNA target sites. The 16S rrna methylases were supposed to have originated from a self-defense mechanism in aminoglycoside-producing actinomycetes, however, the different G + C content of the methylase genes between Gram-negative bacilli and actinomycetes challenged this theory. The true origination of these six types of methylases requires further study. The selection pressure exerted by a variety of antibiotics will therefore promote the dissemination of genetic elements encoding the methylases. Because of the clinical importance of these enzymes, the further global dissemination of 16S rrna methylase genes among pathogenic bacilli will be a cause of great concern in the near future. This review is about the mechanism of resistance, classification, genetic environment, and epidemiology of 16S rrna methylase. Key words: 16S rrna methylase; Plasmid; Aminoglycoside : :, yuxing_ni@ yahoo. com. cn Corresponding author: NI Yu-Xin, yuxing_ni@ yahoo. com. cn,, 30S 16S rrna

2 Journal of Microbes and Infection, March 2009, Vol. 4, No. 1 A,,,, 16S rrna, 1 16S rrna 4 [ 1] : ;, ( aminoglycoside acetyltransferase, AAC) ( aminoglycoside nucleotidyltransferase, ANT AAD) ( aminoglycoside phosphotransferase, APH) ; 16S rrna ;, ( arbekacin),, 6 2", [ 2] 6 -N- -2 -O-, S-,, 16S rrna 16S rrna,, [ 3 ] [ 4-6] 16S rrna 4, 6- - ( 4, 6- disubstituted deoxystreptamine aminoglycoside),,, 16S rrna 2 16S rrna 6 16S rrna, arma rmta rmtb rmtc rmtd npma 2. 1 arma arma BM4536 [ 3 ] /,, 5-episisomicin, 2-6 -N-ethylnetilmicin, - ant3 9, aac3- arma arma Tn1548, IncL/ M [ 7], IncN [ 4] arma bla CTX-M [ 8], ArmA CTX-M [ 9 ], Liou [ 10], arma ArmA 16S rrna N7-G1405, 4, 6-3, G1405 G1405,, ArmA, Agr ( aminoglycoside resistance) ( GrmA GrmB FmrO Sgm Kgm Kmr NbrB KgmB MagrA) arma G + C 30%, G + C > 60%, arma arma 2. 2 rmta,, 16S rrna, rma [ 1 1], Tn5041 rma [ 12], AR-2, rma ( 1)

3 Journal of Microbes and Infection, March 2009, Vol. 4, No trna orfa; rma Na + / H + ( 2) rmta 6. 2 kb, 262 bp orfq rmta AR-11, rmta 2, orfa 5, IS6100 rmta orfq-orfi rmta G + C 55%, 16S rrna G + C 64% 72%, rmta 2. 3 rmtb rmtb [ 13 ] S-95 ( MIC > mg/ L),, RmtA 82%, 16S rrna, rmtb, Tn3 RmtB RmtA, 4, 6- -, RmtB 16S rrna, 33% 2. 4 rmtc rmtc [ 14], 16S rrna, G + C 41. 1% RmtC 16S rrna ( ArmA RmtA RmtB ),, ( 29% ), 16S rrna ( 28% ) rmtc ISEcp1 [ 14, 15 ], tnpa, rmtc 2. 5 rmtd rmtd, SPM-1 [ 16] rmtd G + C 59%, RmtB 42%, RmtA 40% RmtD, rmtd 2. 6 npma npma, ARS3 [ 17 ] NpmA 16S rrna KamA, 30% 4, 6- -, 4, 5- -, NpmA N-1, 16S rrna A A S rrna RNA, 16S rrna 9, 6 ( 1), 9 RNA A m 5 C1407, 2 16S rrna 1 KamA, istamycin Streptomyces tenjimariensis, A1408 N-1 2 GmrA, G1405 N-7 7-, ( Micromonospora 1 16S rrna Fig 1. Dendrogram of 16S rrna methylases

4 Journal of Microbes and Infection, March 2009, Vol. 4, No. 1 purpurea) GmrA Agr, Agr MagrA, Agr, AdoMet, arma rmta rmtb rmtc rmtd npma Agr,,, 6 16S rrna [ 8, 9, ], [ 3, 21 ], [ 16 ],,,,, 4 16S rrna,,,,, [ 1] Davies J, Wright GD. Bacterial resistance to aminoglycoside antibiotics[ J]. Trends Microbiol, 1997, 5( 6) : [ 2] Tanaka N, Matsunaga K, Hirata A, et al. Mechanism of action of arbekacin, a novel amino acid-containing aminoglycoside antibiotic [ J]. Antimicrob Agents Chemother, 1983, 24( 5) : [ 3] Beauclerk AA, Cundliffe E. Sites of action of two ribosomal RNA methylases responsible for resistance to aminoglycosides[ J]. J Mol Biol, 1987, 193( 4) : [ 4] Galimand M, Courvalin P, Lambert T. Plasmid-mediated high level resistance to aminoglycosides in Enterobacteriaceae due to 16S rrna methylation [ J]. Antimicrob Agents Chemother, 2003, 47( 8) : [ 5] Gonz lez-zorn B, Teshager T, Casas M, et al. arma and aminoglycoside resistance in Escherichia coli[ J]. Emerg Infect Dis, 2005, 11( 6) : [ 6] Yamane K, Wachino J, Doi Y, et al. Global spread of multiple aminoglycoside resistance genes [ J]. Emerg Infect Dis, 2005, 11( 6) : [ 7] Galimand M, Sabtcheva S, Courvalin P, et al. Worldwide disseminated arma aminoglycoside resistance methylase gene is borne by composite transposon Tn1548 [ J]. Antimicrob Agents Chemother, 2005, 49( 7) : [ 8] Yan JJ, Wu JJ, Ko WC, et al. Plasmid-mediated 16S rrna methylases conferring high-level aminoglycoside resistance in Escherichia coli and Klebsiella pneumoniae isolates from two Taiwanese hospitals[ J]. J Antimicrob Chemother, 2004, 54( 6) : [ 9] Lee H, Yong D, Yum JH, Roh KH, et al. Dissemination of 16S rrna methylase-mediated highly amikacinresistant isolates of Klebsiella pneumoniae and Acinetobacter baumannii in Korea[ J]. Diagn Microbiol Infect Dis, 2006, 56( 3) : [ 10] Liou GF, Yoshizawa S, Courvalin P, et al. Aminoglycoside resistance by ArmA-mediated ribosomal 16S methylation in human bacterial pathogens[ J]. J Mol Biol, 2006, 359( 2) : [ 11] Yokoyama K, Doi Y, Yamane K, et al. Acquisition of 16S rrna methylase gene in Pseudomonas aeruginosa[ J]. Lancet, 2003, 362( 9399) : [ 12] Yamane K, Doi Y, Yokoyama K, et al. Genetic environments of the rmta gene in Pseudomonas aeruginosa clinical isolates [ J]. Chemother, 2004, 48( 6) : Antimicrob Agents [ 13] Doi Y, Yokoyama K, Yamane K, et al. Plasmid-mediated 16S rrna methylase in Serratia marcescens conferring high-level resistance to aminoglycosides[ J]. Antimicrob Agents Chemother, 2004, 48( 2) : [ 14] Wachino J, Yamane K, Shibayama K, et al. Novel plasmid-mediated 16S rrna methylase, RmtC, found in a Proteus mirabilis isolate demonstrating extraordinary high-level resistance against various aminogycosides[ J]. Antimicrob Agents Chemother, 2006, 50( 1) : [ 15] Wachino J, Yamane K, Kimura K, et al. Mode of transposition and expression of 16S rrna methyltransferase gene rmtc accompanied by ISEcp1 [ J]. Antimicrob Agents Chemother, 2006, 50( 9) : [ 16] Doi Y, Garcia DO, Adams J, et al. Coproduction of novel 16S rrna methylase RmtD and metallo- -lactamase SPM-1 in a panresistant Pseudomonas aeruginosa isolate from Brazil[ J]. Antimicrob Agents Chemother, 2007, 51 ( 3) : ( 58 )

5 ( 48 ) [ 17] Wachino J, Shibayama K, Kurokawa H, et al. Novel plasmid-mediated 16S rrna m 1 A1408 methyltransferase, NpmA, found in a clinically isolated Escherichia coli strain resistant to structurally diverse aminoglycosides[ J]. Antimicrob Agents Chemother, 2007, 51( 12) : [ 18] Yu YS, Zhou H, Yang Q, et al. Widespread occurrence of aminoglycoside resistance due to ArmA methylase in imipenem-resistant Acinetobacter baumannii isolates in China[ J]. J Antimicrob Chemother, 2007, 60( 2) : [ 19] Chen L, Chen ZL, Liu JH, et al. Emergence of RmtB methylase-producing Escherichia coli cloacae isolates from pigs in China[ J]. Chemother, 2007, 59( 5) : and Enterobacter J Antimicrob [ 20] Wu Q, Zhang Y, Han L, et al. Plasmid-mediated 16S rrna methylases in aminoglycoside resistant Enterobacteriaceae in Shanghai, China[ J]. Agents Chemother, 2009, 53( 1) : Antimicrob [ 21] Gonz lez-zorn B, Catalan A, Escudero JA, et al. Genetic basis for dissemination of arma [ J]. Chemother, 2005, 56( 3) : J Antimicrob ( : )

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