Research Progress on the Oxazolidinone Drug Linezolid Resistance

Home , Lincomycin

European Review for Medical and Pharmacological Sciences 2020; 24: 9274-9281 Research progress on the oxazolidinone drug linezolid resistance

B.-G. LIU1,2, X.-L. YUAN3, D.-D. HE4, G.-Z. HU4, M.-S. MIAO1, E.-P. XU1

1Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, China 2Key Laboratory for Modern Research on Zhongjing’s Herbal Formulae of Henan Province, Zhengzhou, China 3Neonatal Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China 4College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, China

Abstract. – OBJECTIVE: The oxazolidinone Introduction drug linezolid is mainly used for severe infections caused by multidrug-resistant Gram-pos- Since the application of antibiotics in the clin- itive bacteria. However, emerging linezolid re- ic, they have played an important role in the sistance is aggravating difficulties in the treatment of certain infectious diseases. The objec- prevention and treatment of diseases. However, tive of this review was to provide a reference for the problem of bacterial resistance has gradually researchers and clinicians to be able to better emerged and is becoming increasingly serious, face together the serious challenge of antimi- complicating clinical treatment1. Due to inexpe- crobial resistance. dient use of antibiotics, such as large doses and MATERIALS AND METHODS: A systematic abuse, the development of bacterial resistance is literature search was performed using PubMed, accelerated, and several unique resistance mech- Web of Science, Google Scholar, and the China National Knowledge Infrastructure (CNKI) data- anisms cause the rapid spread of multi-drug base. The articles were scrutinized to extract in- resistant (MDR) strains, further aggravating the formation on oxazolidinone drug linezolid re- difficulty of disease treatment and posing a po- sistance, and the prevalence of the resistance tential threat to public health2-4. gene optrA. We reviewed the latest advances Oxazolidinone, a new type of antimicrobial in epidemic properties, resistance mechanism, agent, achieves antibacterial effect mainly by in- and transfer mechanism of linezolid resistance genes in different isolates isolated from various hibiting the synthesis of bacterial proteins. Oxazo- samples worldwide. lidinone is often used for severe infections caused RESULTS: Initially, it was thought that linezol- by Gram-positive bacteria, especially for infec- id resistance was related to the change in drug tions caused by MDR bacteria, such as methicil- target mediated by mutations in the 23S rRNA lin-resistant Staphylococcus aureus (MRSA), van- gene, rplC, rplD, and cfr. optrA was discovered comycin-resistant Enterococci (VRE), and Strep- in 2015, and is a gene encoding oxazolidinone tococcus pneumoniae5,6. It has been proposed that resistance, which exists in both plasmids and chromosomes, but mostly plasmids. The emer- the main reason for drug resistance is overuse of 7 gence of the novel plasmid-borne ABC trans- the drug . In 2015, Chinese researchers discovered porter gene optrA expanded the understanding the drug resistance gene optrA8. The gene not only of the mechanism of linezolid resistance. mediates oxazolidinone (linezolid) resistance, but CONCLUSIONS: At present, the prevalence also mediates phenylpropanol (such as flurbenicol) of linezolid resistance has become increasingly resistance, which can be transmitted horizontally. serious. The resistance gene optrA has been reported in Enterococcus, Staphylococcus squir- At present, many scholars in China and abroad rel and Streptococcus, which indicates that this have paid close attention to the prevalence and gene has a strong ability to spread across bac- drug resistance of optrA gene. teria, so the prevalence and spread of optrA In this study, we reviewed data on the optrA gene should be monitored carefully. gene for linezolid resistance, with a view to

Key Words: summarize theoretical scientific basis for rational Oxazolidinone, Linezolid, Resistance gene, OptrA. clinical drug selection and for the prevention of the spread of drug-resistant strains.

Corresponding Authors: Ming-San Miao, Ph.D; e-mail: [email protected] 9274 Er-Ping Xu, Ph.D; e-mail: [email protected] Research progress on the oxazolidinone drug linezolid resistance

Overview of Oxazolidinone Drugs and bic bacteria14. However, due to the effect of the Their Resistance efflux pump system of Gram-negative bacteria, linezolid has little or no antibacterial effect on A Brief Introduction to Oxazolidinone Gram-negative bacteria15. and Linezolid Oxazolidinones comprise a new class of syn- Emergence and Prevalence of thetic antimicrobial drugs, following in the wake Linezolid Resistant Strains of sulfanilamide and fluoroquinolones. Linezolid Because of the unique antibacterial effect of was the first pharmacologically active compound linezolid, resistance towards this drug should developed and the first synthetic oxazolidinone not readily develop in clinical practice. However, approved for clinical use9. Linezolid was ap- with the extensive application of the drug, bac- proved by the US Food and Drug Administration terial resistance to linezolid has been observed (FDA), entered the market in the United States in clinical and in-vitro studies, which has given in 2000, and has mainly been used for severe rise to great concern. In 2000, only one year after infections due to MRSA, VRE, and Streptococ- the drug entered the market, linezolid-resistant cus pneumoniae5. In 2007, it was used in clinical strains emerged, and so, the first clinical strain practice. The oxazolidinones are fully synthetic of linezolid-resistant MRSA was reported in the antibacterial agents, achieving antibacterial effect United States in 2001. By sequencing analysis, it by inhibiting the synthesis of bacterial protein, was verified that the strain had a G2576T point usually with a good effect on infections caused by mutation in the 23S rRNA domain V region, Gram-positive bacteria and MDR bacteria6. resulting in drug resistance to linezolid16. In addition, Staphylococcus aureus resistant to linezolid Overview of the Antibacterial was detected in the first year upon its release in Activity and Mechanism of China17. After that, linezolid-resistant Staphylo- the Oxazolidinone Drug Linezolid coccus was reported in the United States18, Mex- Linezolid can be combined with the peptidyl ico19, Japan 20, Spain21 and Italy22. transferase center (PTC) of the 50S ribosomal subunit of bacteria, which is an inhibitor of bac- Overview of Bacterial Drug Resistance terial protein synthesis and thus plays a critical Induced by the Oxazolidinone antibacterial role10. Compared with chloramphen- Drug Linezolid and its Mechanism icol and lincomycin, linezolid mainly targets the initial phase of protein synthesis, which, however, Induced Resistance does not affect the prolongation or termination of Upon serial passage of methicillin-susceptible the peptide chain during protein synthesis. Even S. aureus and MRSA in linezolid, Locke et al23 if they overlap or are close to the action sites of demonstrated that the minimum inhibitory con- other antimicrobials, they can induce antimicro- centration (MIC) of MRSA and MSSA increased bial activity by inhibiting the translocation of the by 32 and 64 times in 30 generations, respec- peptide chain11. tively. Xi 24 induced Enterococcus with 1/2 MIC Linezolid has exhibited good antibacterial linezolid and found that Enterococcus faecalis effect on MDR Gram-positive bacteria (such as generally developed drug resistance more slowly MRSA). It has been demonstrated that linezolid than Enterococcus faecalis. According to one has a strong bactericidal effect on most species report, after 35 generations, the MIC of oxazolid- and strains of Staphylococcus and Strepto- inone-induced Staphylococcus aureus increased coccus, but only has a bacteriostatic effect on 4-32 times. However, after only 16 generations of Enterococcus. In addition, according to the Enterococcus faecalis induced by oxazolidinone, results of the time-sterilization curve, the ef- the increase in MIC was 8-32 times. Thus, the ficacy of linezolid was found to correlate with fact that members of the same class of antibiotics time; that is, continuous use of the drug could may show different results in terms of inducing be conducive to the improvement of efficacy12. drug resistance in bacteria of the same genus Linezolid has been reported to inhibit some suggests that such bacteria may have diverse and staphylococci and enterococci by 100%13. In complex mechanisms of drug resistance to oxaz- addition, according to in vitro studies, linezol- olidinone antibiotics. id also exhibits certain antibacterial effects Wang et al25 compared MIC values for MR- against Bacillus, gonococci, and some anaero- SA induced by linezolid and vancomycin. After

9275 B.-G. Liu, X.-L. Yuan, D.-D. He, G.-Z. Hu, M.-S. Miao, E.-P. Xu inducing MRSA with 1/2 MIC concentration of positively correlated with the duration of linezol- linezolid and vancomycin for 20 generations, id use. Another study30 found that when linezolid respectively, they found that the MIC of linezolid was administered for more than 20 months, a was 2 mg/L, which was twice the original value, similar pattern was found in clinical strains of while the MIC value of vancomycin increased to S. aureus, in which the T2500A mutation was 4 mg/L, which was four times the original val- observed in multiple copies of the gene. ue. It appears that the rate of MRSA resistance induced by linezolid is similar to that of vanco- Mutations in Ribosomal mycin, with vancomycin being slightly faster in Proteins L3 and L4 terms of reducing resistance in MRSA. The target site of linezolid is the 50S large subunit of the ribosomal proteins, many of which Resistance Mechanisms are closely related to the binding sites of linezol- At present, it is believed that the cause of id drugs, especially the ribosomal proteins L3 linezolid resistance is associated with clinical and L4 which are encoded by the genes rplC overuse of the drug7. The suggested drug re- and rplD respectively23. Locke et al31 studied the sistance mechanisms are accounted for in the DNA sequence of the rplC gene and found the following. mutation sites of ribosomal protein L3, named Mutations in the 23S Ribosomal RNA Gene ∆Serl45 and Alal57Arg, which were closely re- Since the V region of the 23S rRNA gene is lated to the action sites of linezolid. In addition, where the action site of linezolid is located, point in a study of S. pneumoniae, a 6-bp deletion was mutations in the region are mainly resulting found in the highly conserved rplD gene encod- in bacterial resistance to rina thiazole amine; ing ribosomal protein L4. When studying the changes in the structure of point mutations can rplD gene of Clostridium perfringens, a single result in the production of drug resistance, and C-T mutation was found at nucleotide position any locus mutation in this area will to a certain 404, resulting in the substitution of glycine with extent affect the rina thiazole amine resistance26. aspartic acid. In conclusion, mutations in ribo- Among these, the 2576 position in the 23S rR- somal proteins L3 and L4 are associated with NA gene was the first mutation found, and the linezolid resistance. most common occurrence of this site can occur in single copy gene or multi-copy genes27. In Non-mutated Mechanism cfr Gene addition, some point mutations in the 23S rR- Mediates Drug Resistance NA genes, such as T2500A, G2603T, G2215A, The cfr gene, initially isolated from Staphylo- C2534T, G2766T, T2504C, and G2247T have coccus sciuri, mainly confers chloramphenicol been reported to be associated with resistance and florfenicol resistance32. In 2005, the cfr gene in clinical strains. However, so far, only G2576T was first detected in clinically isolated MRSA33. and T2500A have been found in clinical isolates In addition, this gene has also been found in the resistant to linezolid16,23, while other point muta- genus Staphylococcus of human origin18. The tions have been found in induced strains. ubiquity of the cfr gene plays an important role Lobritz et al28 showed that under the selection in the spread of drug resistance. In terms of drug pressure of antibiotics, the genes of Protobacteri- resistance mechanism, the cfr gene confers resis- um were replaced by genes from mutant strains. tance through a non-mutated mechanism, which At the same time, in-vitro induction tests also is different from linezolid resistance, which is showed that the number of G2576T mutations linked to gene mutations. Specifically, the cfr increased, and the drug resistance of the bacteria gene belongs to the methylated transferases, increased with the number of times passed after which can act on the binding site of linezolid and introduction of the first G2576U mutation. When methylate at position 2503 of the 23S rRNA gene, an MIC of 2 g/mL linezolid was used to treat thus making bacteria resistant to chlorampheni- patients with S. aureus infection29, the G2576T col, florfenicol and linezolid34. Locke et al35 found mutation was found. After 20 days of linezolid that the cfr gene was identified in clinical linezol- administration, the MIC increased to 8 g/mL, and id-resistant S. aureus isolates, indicating that the there were 2 G2576T mutations in the S. aureus. presence of the cfr gene is another important After 71 days, the MIC reached 32 g/mL, and 5 mechanism of bacterial resistance to linezolid. G2576T mutations were found. This indicated The cfr gene can be carried by plasmids with that the increasing number of G2576T mutations a mobile function, resulting in horizontal spread

9276 Research progress on the oxazolidinone drug linezolid resistance within the genus of Staphylococcus, causing out- repeatedly reported on observations of this gene breaks of infection with resistant bacteria. It was in Enterococcus isolates. Cai et al37 studied reported that 15 patients with linezolid-resistant 1,159 strains of Enterococcus isolated from MRSA were found in the same hospital within 3 Zhejiang, Guangdong, and Henan in China, months, and all linezolid-resistant strains carried and found that nearly 3% of the strains car- the cfr gene36. At the same time, the cfr gene ried the optrA gene. Zhao38 conducted optrA widely exists in various strains, which is a great gene testing in 513 samples from a pig farm in threat to humans. At present, it is difficult to pre- Guangdong, and 17 strains carrying the optrA vent and control this resistance mechanism. gene were detected. At the same time, they found 11 strains of Enterococcus carrying the Other Resistance Mechanisms optrA gene, and most of these were located in Ribosomal protein mutations in the L22 gene plasmids. Cui et al39 studied 2,201 strains of En- is also associated with the rina thiazole amine terococcus collected from the Chinese bacterial resistance mechanisms. Due to the action of L22 resistance monitoring network over a period of near rina thiazole amine sites, L22 protein amino 10 years and found that the detection rate of the acid mutations, deletions, or replacements may optrA gene was 2.0%. They also found that the also affect peptide acyl transferase space struc- positivity rate of the optrA gene increased from ture; hence, it may also be associated with rina 0.4% in 2004 to 3.9% in 2014, and so the posi- thiazole amine resistance. This is S. aureus to tivity rate of this gene appears to be increasing rina thiazole amine other mechanisms of drug year by year. resistance22,23. Since the discovery of the optrA gene in En- terococcus chinensis, the samples of clinical and animal origin have been reported to carry Involvement of the optrA Gene in the gene in several countries. Gawryszewska et Linezolid Resistance al40 detected five optrA-positive strains among 50 clinically derived linezolid resistant Entero- Discovery of the Drug coccus strains. Later, Brenciani et al41 detected Resistance-Conferring Gene optrA optrA gene in two strains among 81 clinical In 2015, unexpectedly high rina thiazole blood-derived Enterococcus isolates; however, amine MIC values in clinical Enterococcus these two strains also contained another linezol- isolates has been found. In order to explore id resistance gene, cfr. Vorobieva et al42 detect- this finding further, the strain plasmid was se- ed the optrA gene in a strain of E. faecalis in quenced. The authors found that the plasmid a gastric sample from Denmark, which also size was 36,331 bp long, carrying the optrA gene contained genes mediating drug resistance to with a size of 1,968 bp, encoding 655 amino aminoglycosides, macrolides, tetracyclines, and acids, and due to the existence of high amino other drugs. In addition to the above countries, acid sequence homology with ABC transport- strains carrying the optrA gene have also been ers, the gene was named optrA8. The plasmid found in clinical Enterococcus strains in Ire- sequence was submitted to GenBank with the land, Malaysia, and the United States. In the accession number KP399637. The optrA gene last few years since 2015, the gene has shown an can be transmitted horizontally. Linezolid is the emerging trend of worldwide. first choice for the treatment of severe infection with some Gram-positive bacteria, especially optrA Is Common in Staphylococcus MRSA infection, but the emergence of this gene The optrA gene has been less studied in poses a safety threat to human health and the Gram-positive bacteria other than Enterococ- development of livestock and poultry breeding cus; until now, only Staphylococcus of origin industry. Therefore, many scientists in China has been reported to carry the optrA gene. Fan and abroad pay close attention to the emergence et al43 studied porcine methicillin-resistant S. and prevalence of the optrA gene. aureus and coagulase-negative staphylococci isolated in 2014 and found that the positivity rate The Drug Resistance Gene optrA is of the optrA gene in coagulase-negative staphy- Prevalent in Enterococcus Isolates lococci was 6.9%; however, no optrA gene was Since the first report of the optrA gene in found in S. aureus. Li et al44 studied 50 strains Enterococcus in 2015, Chinese scholars have of porcine Staphylococcus isolated in 2013, and

9277 B.-G. Liu, X.-L. Yuan, D.-D. He, G.-Z. Hu, M.-S. Miao, E.-P. Xu only one strain of S. sciuri with the optrA gene was located upstream and/or downstream of was detected. optrA. Therefore, the optrA gene carried by enterococcal plasmids may be transmitted be- ATP Binding Sites of New Drug-Resistant tween different enterococcal species through Protein OptrA IS1216-mediated recombination48. For the eight In 2015, a new drug-resistant protein optrA strains located on the chromosome carrying the was found in the plasmid of Enterococcus pE349 optrA gene, flanking sequence analysis found in China. OptrA belongs to the ABC protein that there are four strains of bacteria carrying family, which confers resistance to oxazolidinone the optrA gene upstream the transcription regu- and chloramphenicol drugs. At present, as a new latory gene araC; another four strains of bacte- drug-resistant protein, the research into optrA is ria had the optrA gene upstream for florfenicol in the initial stage in China and abroad, and the resistance gene fexA. However, it remains un- function and mechanism of this protein have only clear how the optrA gene was integrated into the been scarcely reported. Since all ABC transport- chromosome48. ers belong to ATP hydrolases, however, there is Similar to Enterococcus, the optrA gene lo- no conclusive evidence on the relationship be- calization in S. sciuri may be present on both tween the hydrolysis of ATP and ABC mediated plasmids and chromosomes. By studying plasmids resistance45. Zhong et al46 showed that two glu- from four S. sciuri strains with optrA, it was found tamic acid (E) loci in the optrA domain exhibited that the plasmid size was about 35 kb and all of ATP hydrolysis activity and demonstrated the the four strains were found to contain a 17,612-bp drug resistance associated with optrA for the first contig containing the resistant gene cluster op- time. After in-depth analysis of the hydrolysis of trA-cfr-ble-aadD-aacA-aphD-fexA and a segment ATP locus mutation which can make the function sequence with another plasmid carrying optrA of optrA mediated antibiotic resistance to further pWo28-3 corresponding almost unanimous in their reduce or lose, the optrA mechanism and ATP area. It was suggested that the optrA plasmid iden- binding sites may provide the theoretical basis for tified in the four S. sciuri strains may have come the future research. from the plasmid pWo28-3, and it is possible that S. sciuri has spread in isolated areas43. Twenty-nine The Mechanism of Transmission and strains optrA strains were subject to genetic analy- Diffusion of Drug Resistance Gene OptrA sis, and the chromosome optrA flanking sequence In recent years, the localization of optrA gene can be divided into six types (I-VI), with type I (n in Enterococcus has been observed on both plas- = 12) and IV being most common (n = 10). The mids and chromosomes. The first identified op- type I contig is shortest, contains only the optrA trA gene in Enterococcus E349 is located in the gene, and is located upstream of the transcription 36-kb plasmid pE349, the plasmid carrying open regulation gene araC. The other five types contain reading frame code box 39, including 21 puta- the araC-optrA area. Type IV is located upstream tive proteins; products of the remaining 18 codes of the optrA-araC, carrying the fexA transposon include the linezolid resistance gene optrA, the Tn558, downstream is mdlB1 and mdlB2, coding florfenicol resistance gene fexA, and plasmid ABC transporters. Transposon Tn558 is in the replication and joint transfer related proteins 7. upstream area of araC-optrA in of types II-VI, but Since the time when optrA was first reported in it remains unknown whether it is associated with China, optrA-positive Enterococcus strains have optrA in S. scirui43. been detected in many countries around the world, and the plasmids carrying optrA genes Drug-Resistant Genes Transfer or detected in clinical and animal-derived strains Pass From One Bacterium to Another in some countries have high similarity to pE349, At present, it is known from many studies that suggesting that there may be human-to-animal some drug-resistant genes can be transferred transmission40,47. It was also reported that 17 or transferred between bacteria. However, this strains of E. faecalis carried optrA (nine strains phenomenon is mainly caused by drug-resistant located in plasmids and eight strains located genes existing in plasmids, and plasmid conju- on chromosomes) were investigated for their gation is an important pathway of gene transfer, genetic environment, and it was found that all most pathogens acquire drug resistance mainly nine plasmids contained the inserted sequence through conjugation49. For example, the MDR IS1216E, belonging to the IS6 family, which gene lsa (E) was first identified in human MRSA

9278 Research progress on the oxazolidinone drug linezolid resistance

ST398 and S. aureus ST9, followed by pig and Prevalence and molecular characterization of human Enterococcus50. At first, amide-alcohol oqxAB in clinical Escherichia coli isolates from resistance gene fexA and MDR gene cfr were companion animals and humans in Henan Prov- ince, China. Antimicrob Resist Infect Control found in Staphylococcus, followed by Entero- 2018; 7: 18. coccus and Streptococcus51. In addition, vanA, 3) Liu BG, Wang BY, Li YC, Bai M, Miao MS, Xu EP. a vancomycin resistant gene, was first identified Gene environmental structure of CTX-M-14 type in Enterococcus, and subsequently also found in ESBL gene produced by Klebsiella pneumoniae. MRSA52. At present, although no optrA gene has Chin J Zoonoses 2019; 35: 950-956. been reported in S. aureus, awareness regarding 4) Licker M, Anghel A, Moldovan R, Hogea E, Munte- the possible introduction of optrA in S. aureus is an D, Horhat F, Seclaman E, Tamas L, Anghel M, Ba- ditoiu L recommended. . Genotype-phenotype correlation in mul- tiresistant Escherichia coli and Klebsiella pneumoniae strains isolated in Western Romania. Eur Conclusions and Future Prospects Rev Med Pharmacol Sci 2015; 19: 1888-1894. OptrA, a novel gene for resistance to the oxaz- 5) Brickner SJ, Barbachyn MR, Hutchinson DK, Mannin- olidinone linezolid, not only mediates linezolid en PR. Linezolid (ZYVOX), the first member of a resistance but also florfenicol resistance, which is completely new class of antibacterial agents for mostly present in plasmids and can be transmit- treatment of serious gram-positive infections. J ted horizontally, further exacerbating the rate of Med Chem 2008; 51: 1981-1990. Jadhavar PS, Vaja MD, Dhameliya TM, Chakrabor- transmission53. Linezolid is the first-line drug in 6) ti AK. Oxazolidinones as anti-tubercular agents: the clinical treatment of some serious infections discovery, development and future perspectives. due to major drug-resistant bacteria such as MR- Curr Med Chem 2015; 22: 4379-4397. SA and VRE; therefore, the emergence and rapid 7) Ikeda-Dantsuji Y, Hanaki H, Nakae T, Takesue Y, To- spread of this gene has attracted the attention mono K, Honda J, Yanagihara K, Mikamo H, Fukuchi of medical doctors and scientists in China and K, Kaku M, Kohno S, Niki Y. Emergence of linezol- abroad54-56. id-Resistant mutants in a susceptible-cell popul- mion of methicillin-resistant Staphylococcus au- Although there are some differences in the ge- reus. Antimicrob Agents Chemother 2011; 55: netic background of optrA gene, there is a certain 2466-2468. possibility of human and animal transmission and 8) Wang Y, Lv Y, Cai JC, Schwarz S, Cui LQ, Hu ZD, thereby worldwide dissemination of this gene. Zhang R, Li J, Zhao Q, He T, Wang DC, Wang Z, Therefore, vigilance is needed. Shen YB, Li Y, Fessler AT, Wu CM, Yu H, Deng XM, Xia X, Shen JZ. A novel gene, optrA, that confers transferable resistance to oxazolidinones and phenicols and its presence in Enterococcus fae- Conflict of Interest calis and Enterococcus faecium of human and The Authors declare that they have no conflict of interests. animal origin. J Antimicrob Chemother 2015; 70: 2182-2190. 9) Li J, Zhao QH, Huang KC, Li ZQ, Zhang LY, Qin DY, Pan F, Huang WX. Linezolid vs. vancomycin in Acknowledgements treatment of methicillin-resistant staphylococcus This study was supported by grants from the National aureus infections: a meta-analysis. Eur Rev Med Natural Science Foundation of China (No. 81973739), the Pharmacol Sci 2017; 21: 3974-3979. Henan Post-doctoral Research Project Start-up Funding Shinabarger DL, Marotti KR, Murray RW, Lin AH, (No. 19030075), the Henan of Chinese Medicine Special 10) Melchior EP, Swaney SM, Dunyak DS, Demyan WF, Research Project (No. 2019ZY1019; 20-21ZY2144), and the Buysse JM Henan University of Chinese Medicine Research Start-up . Mechanism of action of oxazolidi- Funding (No. RSBSJJ2018-11). nones: effects of linezolid and eperezolid on translation reactions. Antimicrob Agents Chemo- ther 1997; 41: 2132-2136. 11) Bobkova EV, Yan YP, Jordan DB, Kurilla MG, Pompli- References ano DL. Catalytic properties of mutant 23S ribo- somes resistant to oxazolidinones. J Biol Chem 1) Liu BG, Sun HR, Pan YS, Zhai YJ, Cai T, Yuan XL, Gao 2003; 278: 9802-9807. YL, He DD, Liu JH, Yuan L, Hu GZ. Prevalence, an- 12) Zhu DM, Zhang YY, Zhou L, Wu PC, Hu FP, Wu WH, timicrobial resistance, and molecular character- Wu S, Wang F. In vitro activities of linezolid against ization of Staphylococcus aureus isolates from clinical isolates. Chin J Infect Chemother 2008; 8: animals and humans in Henan Province, China. 81-88. Gut Pathog 2018; 10: 31. 13) Zhou WC. Progress of research on antibacterial 2) Liu BG, Wu H, Zhai YJ, He ZP, Sun HR, Cai T, He agents inhibiting bacterial protein synthesis. Chin DD, Liu JH, Wang SM, Pan YS, Yuan L, Hu GZ. J Pharm 2007; 38: 805-813.

9279 B.-G. Liu, X.-L. Yuan, D.-D. He, G.-Z. Hu, M.-S. Miao, E.-P. Xu

14) Holzel CS, Harms KS, Schwaiger K, Bauer J. Resis- icoplanin and linezolid. J Dalian Med Univer 2012; tance to linezolid in a porcine Clostridium perfrin- 34: 257-261. gens strain carrying a mutation in the rplD gene 26) Bonilla H, Huband MD, Seidel J, Schmidt H, Lescoe encoding the ribosomal protein L4. Antimicrob M, McCurdy SP, Lemmon MM, Brennan LA, Tait-Kam- Agents Chemother 2010; 54: 1351-1353. radt A, Puzniak L, Quinn JP. Multicity outbreak 15) Schumacher A, Trittler R, Bohnert JA, Kummerer K, of linezolid-resistant Staphylococcus epidermidis Pages JM, Kem WV. Intracellular accumulation of associated with clonal spread of a cfr-containing linezolid in Escherichia coli, Citrobacter freundii strain. Clin Infect Dis 2010; 51: 796-800. and Enterobacter aerogenes: role of enhanced 27) Li BB, Wu CM, Wang Y, Shen JZ. Single and du- efflux pump activity and inactivation. J Antimicrob al mutations at positions 2058, 2503 and 2504 of Chemother 2007; 59: 1261-1264. 23S rRNA and their relationship to resistance to 16) Tsiodras S, Gold HS, Sakoulas G, Eliopoulos GM, antibiotics that target the large ribosomal subunit. Wennersten C, Venkataraman L, Jr RCM, Ferra- J Antimicrob Chemother 2011; 66: 1983-1986. ro MJ. Linezolid resistance in a clinical isolate of 28) Lobritz M, HuRon-Thomas R, Marshall S, Rice LB. staphylococcus aureus. Lancet 2001; 358: 207- Recombination proficiency influences frequen- 208. cy and locus of mutational resistance to linezol- 17) Jones RN, Fritsche TR, Sader HS, Ross JE. LEADER id in Enterococcus faecalis. Antimicrob Agents surveillance program results for 2006: an activity Chemother 2003; 47: 3318-3320. and spectrum analysis of linezolid using clinical 29) Wilson P, Andrews JA, Charlesworth R, Walesby R, isolates from the United States (50 medical cen- Singer M, Farrell DJ, Robbins M. Linezolid resistan- ters). Diagn Microb Infect Dis 2007; 59: 309-317. te in clinical isolates of Staphylococcus aureus. J 18) Mendes RE, Deshpande LM, Castanheira M, DiPersio Antimicrob Chemother 2003; 51: 186-188. J, Saubolle MA, Jones RN . First report of cfr-me- 30) Meka VG, Pillai SK, Sakoulas G, Wennersten C, Ven- diated resistance to linezolid in human staphy- kataraman L, DeGirolami PC, Eliopoulos GM, Jr lococcal clinical isolates recovered in the United RCM, Gold HS. Linezolid resistance in sequential States. Antimicrob Agents Chemother 2008; 52: Staphylococcus aureus isolates associated with 2244-2246. a T2500A mutation in the 23S rRNA gene and 19) Mendes RE, Deshpande L, Rodriguez-Noriega E, Ross loss of a single copy of rRNA. J Infect Dis 2004; JE, Jones RN, Morfin-Otero R. First report of 190: 311-317. Staphylococcal clinical isolates in Mexico with 31) Locke JB, Hilgers M, Shaw KJ. Mutations in ribosom- linezolid resistance caused by cfr: evidence of al protein L3 are associated with oxazolidinone re- in vivo cfr mobilization. J Clin Microb 2010; 48: sistance in Staphyococci of clinical origin. Antimi- 3041-3043. crob Agents Chemother 2009; 53: 5275-5278. Ikeda-Dantsuji Y, Hanaki H, Sakai F, Tomono K, Take- 20) 32) Schwarz S, Werckenthin C, Kehrenberg C. Identifica- sue Y, Honda J, Nonomiya Y, Suwabe A, Nagura O, tion of a plasmid-borne chloramphenicol-florfeni- Yanagihara K, Mikamo H, Fukuchi K, Kaku M, Kohno col resistance gene in Staphylococcus sciuri. An- S, Yanagisawa C, Nakae T, Yoshida K, Niki Y. Linezol- timicrob Agents Chemother 2000; 44: 2530-2533. id-resistant Staphylococcus aureus, isolated from 33) Toh SM, Xiong LQ, Arias CA, Villegas MV, Lolans 2006 through 2008 at six hospitals in Japan. J In- K, Quinn J, Mankin AS. Acquisition of a natural re- fect Chemother 2011; 17: 45-51. sistance gene renders a clinical strain of meticil- Seral C, Saenz Y, Algarate S, Duran E, Luque P, Tor- 21) lin-resistant Staphylococcu saureus resistant to res C, Castillo FJ . Nosocomial outbreak of methi- the synthetic antibiotic linezolid. Mol Microb 2007; cillin-and linezolid-resistant Staphylococcus epi- 64: 1506-1514. dermidis associated with catheter-related infec- 34) Locke JB, Finn J, Hilgers M, Morales G, Rahawi S, tions in intensive care unit patients. Int J Med Mi- Kedar GC, Picazo JJ, Im W, Shaw KJ, Stein JL. Struc- crob 2011; 301: 354-358. ture-activity elationships of diverse oxazolidi- Mendes RE, Deshpande LM, Farrell DJ, Spanu T, 22) nones for linezolid-resistant Staphylococcus au- Fadda G, Jones RN . Assessment of linezolid resis- reus strains possessing the cfr methyltransferase tance mechanisms among staphylococcus epi- gene or ribosomal mutations. Antimicrob Agents dermidis causing bacteraemia in Rome, Italy. J Chemother 2010; 54: 5337-5343. Antimicrob Chemother 2010; 65: 2329-2335. 35) Locke JB, Morales G, Hilgers M, Kedar GC, Raha- Locke JB, Hilgers M, Shaw KJ. 23) Novel ribosom- wi S, Picazo JJ, Shaw KJ, Stein JL. Elevmed linezol- al mutations in Staphylococcus aureus strains id resistance in clinical cfr-positive Staphylococ- identified through selection with the oxazolidi- cus aureus isolates is associated with co-occur- nones linezolid and torezolid (TR-700). Antimi- ring mutations in ribosomal protein L3. Antimicrob crob Agents Chemother 2009; 53: 5265-5274. Agents Chemother 2010; 54: 5352-5355. Xi R. 24) The study on resistance mechanism of en- 36) Morales G, Picazo JJ, Baos E, Candel FJ, Arribi A, terococci by linezolid in vitro. China medical uni- Pelaez B, Andrade R, Torre MADL, Fereres J, San- versity, 2010. chez-Garcia M. Resistance to linezolid is mediated 25) Wang YY, Wang ZS, Xue X, Nie DP. Comparison on by the cfr gene in the first report of an outbreak of in-vitro induction of resistance in methicillin-resis- linezolid-resistant Staphlococcus aureus. Clin In- tance Staphylococcus Aureus to vancomycin, te- fect Dis 2010; 50: 821-825.

9280 Research progress on the oxazolidinone drug linezolid resistance

37) Cai JC, Wang Y, Schwarz S, Lv H, Li Y, Liao K, Yu K, 47) Cavaco LM, Bernal JF, Zankari E, Leon M, Hen- Zhao K, Gu D, Wang X, Zhang R, Shen JZ. Entero- driksen RS, Perez-Gutierrez E, Aarestrup FM, Dona- coccal isolates carrying the novel oxazolidinone do-Godoy P. Detection of linezolid resistance due resistance gene optrA from hospitals in Zhejiang, to the optrA gene in Enterococcus faecalis from Guangdong, and Henan, China, 2010-2014. Clin poultry meat from the American continent (Co- Microb Infect 2015; 21: 1091-1095. lombia). J Antimicrob Chemother 2017; 72: 678- 38) Zhao LQ. The epidemic characteristics of oxaz- 683. olidinone-resistant gene optrA in a pig farm in 48) He T, Shen YB, Schwarz S, Cai JC, Lv Y, Li J, Fessler Guangdong[D]. South China agricultural universi- AT, Zhang R, Wu CM, Shen JZ, Wang Y. Genetic ty, 2016. environment of the transferable oxazolidinone/ 39) Cui LQ, Wang Y, Lv Y, Wang S, Song YJ, Li Y, Liu phenicol resistance gene optrA in Enterococcus J, Xue F, Yang WW, Zhang J. Nationwide surveil- faecalis isolates of human and animal origin. J lance of novel oxazolidinone resistance gene op- Antimicrob Chemother 2016; 71: 1466-1473. trA in enterococcus isolates in China from 2004 49) Chen YJ, Pei YL, Pan YS, Wu H, Liu JH, Yuan L, Du to 2014. Antimicrob Agents Chemother 2016; 60: XD, Meng CP, Hu GZ. Detection of aminoglycoside 7490-7493. resistance gene in Escherichia coli isolates from 40) Gawryszewska I, Zabicka D, Hryniewicz W, Sadowy ducks and its dissemination mechanism. Chin J E. Linezolid-resistant enterococci in Polish hos- Zoonoses 2013; 29: 138-141. pitals: species, clonality and determinants of 50) Si HB, Zhang WJ, Chu SB, Wang XM, Dai L, Hua linezolid resistance. Eur J Clin Microb Infect Dis X, Dong ZM, Schwarz S, Liu SG. Novel plas- 2017; 36: 1279-1286. mid-borne multidrug resistance gene cluster 41) Brenciani A, Morroni G, Vincenzi C, Manso E, Min- including lsa(E) from a linezolid-resistant En- goia M, Giovanetti E, Varaldo PE. Detection in It- terococcus faecium isolate of swine origin. An- aly of two clinical Enterococcus faecium iso- timicrob Agents Chemother 2015; 59: 7113- lates carrying both the oxazolidinone and phen- 7116. icol resistance gene optrA and a silent multi-re- 51) Shen J, Wang Y, Schwarz S. Presence and dis- sistance gene cfr. J Antimicrob Chemother semination of the multiresistance gene cfr in 2016; 71: 1118-1119. Gram-positive and Gram-negative bacteria. J An- 42) Vorobieva V, Roer L, Justesen US, Hansen F, Fri- timicrob Chemother 2013; 68: 1697-1706. modt-Moller N, Hasman H, Hammerum AM. Detec- 52) Chang S, Sievert DM, Hageman JC, Boulton ML, tion of the optrA gene in a clinical ST16 Entero- Tenover FC, Downes FP, Shah S, Rudrik JT, Rupp GR, coccus faecalis isolate in Denmark. J Glob Anti- Brown WJ, Cardo D, Fridkin SK. Infection with van- microb Resist 2017; 10: 12-13. comycin-resistant Staphylococcus aureus containing the vanA resistance gene. N Engl J Med 43) Fan R, Li DX, Wang Y, He T, Fessler AT, Schwarz 2003; 348: 1342-1347. S, Wu CM. Presence of the optrA gene in methicillin-resistant Staphylococcus sciuri of porcine 53) Cui LQ, Lv Y. Advances in novel linezolid resis- origin. Antimicrob Agents Chemother 2016; 60: tance gene optrA. Chin J Microb Immunol 2017; 7200-7205. 37: 709-711. 44) Li DX, Wang Y, Schwarz S, Cai JC, Fan R, Li J, Fessler 54) Liu LL, Zhang JY. Advances on oxazolidi- AT, Zhang R, Wu CM, Shen JZ. Co-location of the none-quinolone hybrids. Chin J Animal Veter Sci oxazolidinone resistance genes optrA and cfr on a 2018; 49: 10-17. multiresistance plasmid from Staphylococcus sci- 55) Abad L, Tafani V, Tasse J, Josse J, Chidiac C, Lustig S, uri. J Antimicrob Chemother 2016; 71: 1474-1478. Ferry T, Diot A, Laurent F, Valour F. Evaluation of 45) Jacquet E, Girard JM, Ramaen O, Pamlard O, Levai- the ability of linezolid and tedizolid to eradicate que H, Betton JM, Dassa E, Chesneau O. ATP hydro- intraosteoblastic and biofilm embedded Staphy- lysis and pristinamycin IIA inhibition of the Staph- lococcus aureus in the bone and joint infection ylococcus aureus vga(A), a dual ABC protein in- setting. J Antimicrob Chemother 2019; 74: 625- volved in streptogramin A resistance. J Biolog 632. Chem 2008; 283: 25332-25339. 56) Kramer TS, Schwab F, Behnke M, Hansen S, Gastmei- 46) Zhong XB, Wang L, Wang TD, Zhong L, Wang DC. er P, Aghdassi SJS. Linezolid use in German acute Confirmation of two key active sites of the new care hospitals: results from two consecutive na- drug resistance protein OptrA. Chin J Vet Sci tional point prevalence surveys. Antimicrob Re- 2017; 37: 717-720. sist Infect Control 2019; 8: 159.

9281