Comparison of antibacterial activities and resistance mechanisms of omadacycline and tigecycline against enterococcus faecium

ABSTRACT This study aims to compare the antimicrobial activity of omadacycline with tigecycline against clinical isolates of _Enterococcus faecium_ and investigate their resistance

mechanisms. Non-duplicate clinical _E. faecium_ isolates (_n_ = 224) were collected and the minimal inhibitory concentrations (MICs) of omadacycline and tigecycline were determined by broth

microdilution method. The _tet_ genes and the genetic mutations in 16 S rRNA genes and 30 S ribosomal protein S10 were determined by PCR and sequence alignment. The global protein abundances

of the omadacycline-induced and parent isolates were determined by a Q Exactive plus mass spectrometer. The MIC50/MIC90 of omadacycline and tigecycline against the 224 _E. faecium_ isolates

were 0.25/0.5 mg l−1 and 0.125/0.25 mg l−1, respectively. Among these _E. faecium_ isolates, the frequency of the isolates with omadacycline MICs ≥ 0.25 mg l−1 were significantly higher

than that with tigecycline MICs ≥ 0.25 mg l−1. Moreover, the T1473C and/or G1468A mutations in the 16 S rRNA and Lys98Glu mutation in the 30 S ribosomal protein S10 were identified in the 3

series of tigecycline or omadacycline- nonsusceptible isolates selected in vitro. The abundances of 32 proteins changed in the omadacycline-induced isolate, of which 10 increased and 22

decreased. The abundance of _tet_(M) increased significantly in the omadacycline-induced isolate, and the abundance of proteins included in cellular process and metabolic process decreased.

In conclusion, Omadacycline and tigecycline exhibits excellent activities against clinical isolates of _E. faecium_ and exposure to omadacycline and tigecycline can result in significant

cross-resistance to both antibiotics. The high-level expression of _tet_(M) in _E. faecium_ may confer resistance to omadacycline. Access through your institution Buy or subscribe This is a

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ACTIVITY OF RADEZOLID AGAINST _ENTEROCOCCUS FAECIUM_ AND COMPARED WITH LINEZOLID Article 16 July 2020 IN VITRO ACTIVITY AND ADAPTATION STRATEGIES OF ERAVACYCLINE IN CLINICAL _ENTEROCOCCUS

FAECIUM_ ISOLATES FROM CHINA Article 27 July 2022 COMPARISON OF SOLITHROMYCIN WITH ERYTHROMYCIN IN _ENTEROCOCCUS FAECALIS_ AND _ENTEROCOCCUS FAECIUM_ FROM CHINA: ANTIBACTERIAL ACTIVITY,

CLONALITY, RESISTANCE MECHANISM, AND INHIBITION OF BIOFILM FORMATION Article 19 October 2020 DATA AVAILABILITY All data generated or analyzed during this study are included in this published

article [and its supplementary information files]. The mass spectrometry proteomics data were deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset

identifier PXD026325. REFERENCES * Arias CA, Murray BE. The rise of the _Enterococcus_: beyond vancomycin resistance. Nat Rev Microbiol. 2012;10:266–78. Article  CAS  Google Scholar  *

Cattoir V, Giard JC. Antibiotic resistance in _Enterococcus faecium_ clinical isolates. Expert Rev Anti Infect Ther. 2014;12:239–48. Article  CAS  Google Scholar  * Gotfried MH, Horn K,

Garrity-Ryan L, Villano S, Tzanis E, Chitra S, et al. Comparison of omadacycline and tigecycline pharmacokinetics in the plasma, epithelial lining fluid, and alveolar cells of healthy adult

subjects. Antimicrob Agents Chemother. 2017;61:e01135-17. * Nguyen F, Starosta AL, Arenz S, Sohmen D, Dönhöfer A, Wilson DN. Tetracycline antibiotics and resistance mechanisms. Biol Chem.

2014;395:559–75. Article  CAS  Google Scholar  * Cattoir V, Isnard C, Cosquer T, Odhiambo A, Bucquet F, Guérin. et al. Genomic analysis of reduced susceptibility to tigecycline in

Enterococcus faecium. Antimicrob Agents Chemother. 2015;59:239–44. Article  Google Scholar  * Zhanel GG, Esquivel J, Zelenitsky S, Lawrence CK, Adam HJ, Golden A. et al. Omadacycline: a

novel oral and intravenous aminomethylcycline antibiotic agent. Drugs. 2020;80:285–313. Article  CAS  Google Scholar  * Lin Z, Pu Z, Xu G, Bai B, Chen Z, Sun X, et al. Omadacycline efficacy

against _Enterococcus faecalis_ isolated in China: in vitro activity, heteroresistance, and resistance mechanisms. Antimicrob Agents Chemother 2020;64. * Draper MP, Weir S, Macone A,

Donatelli J, Trieber CA, Tanaka, Levy SBSK. Mechanism of action of the novel aminomethylcycline antibiotic omadacycline. Antimicrob Agents Chemother. 2014;58:1279–83. Article  Google Scholar

  * Villano S, Steenbergen J, Loh E. Omadacycline: development of a novel aminomethylcycline antibiotic for treating drug-resistant bacterial infections. Future Microbiol. 2016;11:1421–34.

Article  CAS  Google Scholar  * Tanaka SK, Steenbergen J, Villano S. Discovery, pharmacology, and clinical profile of omadacycline, a novel aminomethylcycline antibiotic. Bioorg Med Chem.

2016;24:6409–19. Article  CAS  Google Scholar  * Pfaller MA, Huband MD, Rhomberg PR, Flamm RK. Surveillance of omadacycline activity against clinical isolates from a global collection (North

America, Europe, Latin America, Asia-Western Pacific), 2010–2011. Antimicrob Agents Chemother. 2017;61. * Niebel M, Quick J, Prieto AM, Hill RL, Pike R, Huber D. et al. Deletions in a

ribosomal protein-coding gene are associated with tigecycline resistance in _Enterococcus faecium_. Int J Antimicrob Agents. 2015;46:572–5. Article  CAS  Google Scholar  * Zhang F, Bai B, Xu

G, Lin Z, Li G, Chen Z. et al. Eravacycline activity against clinical _S. aureus_ isolates from China: in vitro activity, MLST profiles and heteroresistance. BMC Microbiol. 2018;18:211

Article  CAS  Google Scholar  * Bai B, Lin Z, Pu Z, Xu G, Zhang F, Chen Z. et al. In vitro activity and heteroresistance of omadacycline against clinical _Staphylococcus aureus_ isolates

from China reveal the impact of omadacycline susceptibility by branched-chain amino acid transport system II carrier protein, Na/Pi cotransporter family protein, and fibronectin-binding

protein. Front Microbiol. 2019;10:2546 Article  Google Scholar  * Bai B, Hu K, Li H, Yao W, Li D, Chen Z, et al. Effect of tedizolid on clinical _Enterococcus_ isolates: in vitro activity,

distribution of virulence factor, resistance genes and multilocus sequence typing. FEMS Microbiol Lett. 2018;365. * Wiśniewski JR, Zougman A, Nagaraj N, Mann M. Universal sample preparation

method for proteome analysis. Nat Methods. 2009;6:359–62. Article  Google Scholar  * Jernigan JA, Hatfield KM, Wolford H, Nelson RE, Olubajo B, Reddy SC. et al. Multidrug-resistant bacterial

infections in U.S. hospitalized patients, 2012–2017. N. Engl J Med. 2020;382:1309–19. Article  CAS  Google Scholar  * Werner G, Gfrorer S, Fleige C, Witte W, Klare I. Tigecycline-resistant

_Enterococcus faecalis_ strain isolated from a German intensive care unit patient. J Antimicrob Chemother. 2008;61:1182–3. Article  CAS  Google Scholar  * Hoban DJ, Reinert RR, Bouchillon

SK, Dowzicky MJ. Global in vitro activity of tigecycline and comparator agents: Tigecycline Evaluation and Surveillance Trial 2004–2013. Ann Clin Microbiol Antimicrob. 2015;14:27. Article 

Google Scholar  * Karlowsky JA, Steenbergen J, Zhanel GG. Microbiology and preclinical review of omadacycline. Clin Infect Dis : Off Publ Infect Dis Soc Am. 2019;69:S6–15. Article  CAS 

Google Scholar  * Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev.

2001;65:232–60. Article  CAS  Google Scholar  * Macone AB, Caruso BK, Leahy RG, Donatelli J, Weir S, Draper MP. et al. In vitro and in vivo antibacterial activities of omadacycline, a novel

aminomethylcycline. Antimicrob Agents Chemother. 2014;58:1127–35. Article  CAS  Google Scholar  * Ng LK, Martin I, Alfa M, Mulvey M. Multiplex PCR for the detection of tetracycline resistant

genes. Mol Cell Probes. 2001;15:209–15. Article  CAS  Google Scholar  * McAleese F, Petersen P, Ruzin A, Dunman PM, Murphy E, Projan SJ. et al. A novel MATE family efflux pump contributes

to the reduced susceptibility of laboratory-derived _Staphylococcus aureus_ mutants to tigecycline. Antimicrob Agents Chemother. 2005;49:1865–71. Article  CAS  Google Scholar  * Fiedler S,

Bender JK, Klare I, Halbedel S, Grohmann E, Szewzyk U. et al. Tigecycline resistance in clinical isolates of _Enterococcus faecium_ is mediated by an upregulation of plasmid-encoded

tetracycline determinants tet(L) and tet(M). J Antimicrob Chemother. 2016;71:871–81. Article  CAS  Google Scholar  * Beabout K, Hammerstrom TG, Perez AM, Magalhaes BF, Prater AG, Clements

TP. et al. The ribosomal S10 protein is a general target for decreased tigecycline susceptibility. Antimicrob Agents Chemother. 2015;59:5561–5566. Article  CAS  Google Scholar  * Wen Z,

Shang Y, Xu G, Pu Z, Lin Z, Bai B. et al. Mechanism of eravacycline resistance in clinical _Enterococcus faecalis_ Isolates from China. Front Microbiol. 2020;11:916 Article  Google Scholar 

Download references ACKNOWLEDGEMENTS The authors would like to thank Weiguang Pan (Department of Microbiological laboratory, Shenzhen Nanshan people’s Hospital, Shenzhen University of School

Medicine) for his excellent technical support and suggestions. FUNDING This work was supported by the following grants: National Natural Science Foundation of China (No. 81902033); Natural

Science Foundation of Guangdong Province, China (No. 2020A1515011049, 2021A1515011727); Sanming Project of Medicine in Shenzhen (No.SMGC201705029); Shenzhen Key Medical Discipline

Construction Fund (No. SZXK06162); Science, Technology and Innovation Commission of Shenzhen Municipality of key funds (JCYJ20180508162403996) and basic research funds

(JCYJ20180302144431923; JCYJ20180302144721183; JCYJ20180302144340004; JCYJ20180302144345028). AUTHOR INFORMATION Author notes * These authors contributed equally: Xiaoming Liu, Chaoqin

Zhang, Yuxi Zhao, Hang Cheng. AUTHORS AND AFFILIATIONS * Department of Gastroenterology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, 518067, China Xiaoming Liu * Department

of Gastroenterology, Shenzhen Shekou People’s Hospital, Shenzhen, 518067, China Xiaoming Liu * Department of Infectious Diseases and the Key Lab of Endogenous Infection, Huazhong University

of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China Chaoqin Zhang, Yuxi Zhao, Hang Cheng, Yu Wang, Zhanwen Wang, Yongpeng Shang, Jinxin Zheng, Zhijian Yu & Yiyi

Shi * Department of Infectious Diseases and the Key Lab of Endogenous Infection, Shenzhen Nanshan People’s Hospital and The 6th Affiliated Hospital of Shenzhen University Health Science

Center, Shenzhen, 518052, China Chaoqin Zhang, Yuxi Zhao, Hang Cheng, Yu Wang, Zhanwen Wang, Yongpeng Shang, Jinxin Zheng, Zhijian Yu & Yiyi Shi Authors * Xiaoming Liu View author

publications You can also search for this author inPubMed Google Scholar * Chaoqin Zhang View author publications You can also search for this author inPubMed Google Scholar * Yuxi Zhao View

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View author publications You can also search for this author inPubMed Google Scholar * Zhanwen Wang View author publications You can also search for this author inPubMed Google Scholar *

Yongpeng Shang View author publications You can also search for this author inPubMed Google Scholar * Jinxin Zheng View author publications You can also search for this author inPubMed 

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inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to Zhijian Yu or Yiyi Shi. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare no competing interests. ETHICS APPROVAL

All procedures involving human participants were approved by the ethics committee of Shenzhen Shekou People’s Hospital and Shenzhen Nanshan People’s Hospital, in accordance with the ethical

standards of Shenzhen University and the 1964 Helsinki declaration and its later amendments, or comparable ethical standards. Formal consent is not required for such study. ADDITIONAL

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permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Liu, X., Zhang, C., Zhao, Y. _et al._ Comparison of antibacterial activities and resistance mechanisms of omadacycline and tigecycline

against _Enterococcus faecium_. _J Antibiot_ 75, 463–471 (2022). https://doi.org/10.1038/s41429-022-00538-2 Download citation * Received: 07 November 2021 * Revised: 02 June 2022 * Accepted:

05 June 2022 * Published: 27 June 2022 * Issue Date: August 2022 * DOI: https://doi.org/10.1038/s41429-022-00538-2 SHARE THIS ARTICLE Anyone you share the following link with will be able

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