Identification and characterization of two novel IS CR1-associated genes dfrA42 and dfrA43 encoding trimethoprim resistant dihydrofolate reductases

doi:10.1128/AAC.02010-20

. 2023 May 1;95(5):e02010-20.

doi: 10.1128/AAC.02010-20. Epub 2021 Feb 16.

Identification and characterization of two novel IS CR1-associated genes dfrA42 and dfrA43 encoding trimethoprim resistant dihydrofolate reductases

Ling Li¹, Mengge Zhang¹, Wenjia Wang¹, Ruirui Xia¹, Yanan Ma¹, Xin Wei¹, Xinhua Wang², Xiaomin Sun³, Xiaohong Xie⁴, Shiling Xie⁴, Mingyu Wang⁵, Hai Xu⁵

Affiliations

¹ State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, Qingdao, Shandong, China.
² Shandong Provincial Key Laboratory of Water Pollution Control and Resource Reuse, School of Environmental Science and Engineering, Shandong University, Qingdao, Shandong, China.
³ Environmental Research Institute, Shandong University, Qingdao, Shandong, China.
⁴ Shandong Shtars Medical Technology Co., Ltd.
⁵ State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, Qingdao, Shandong, China. wangmingyu@sdu.edu.cn haixu@sdu.edu.cn.

PMID: 33593833
PMCID: PMC8092886
DOI: 10.1128/AAC.02010-20

Identification and characterization of two novel IS CR1-associated genes dfrA42 and dfrA43 encoding trimethoprim resistant dihydrofolate reductases

Ling Li et al. Antimicrob Agents Chemother. 2023.

. 2023 May 1;95(5):e02010-20.

doi: 10.1128/AAC.02010-20. Epub 2021 Feb 16.

Authors

Ling Li¹, Mengge Zhang¹, Wenjia Wang¹, Ruirui Xia¹, Yanan Ma¹, Xin Wei¹, Xinhua Wang², Xiaomin Sun³, Xiaohong Xie⁴, Shiling Xie⁴, Mingyu Wang⁵, Hai Xu⁵

Affiliations

¹ State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, Qingdao, Shandong, China.
² Shandong Provincial Key Laboratory of Water Pollution Control and Resource Reuse, School of Environmental Science and Engineering, Shandong University, Qingdao, Shandong, China.
³ Environmental Research Institute, Shandong University, Qingdao, Shandong, China.
⁴ Shandong Shtars Medical Technology Co., Ltd.
⁵ State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, Qingdao, Shandong, China. wangmingyu@sdu.edu.cn haixu@sdu.edu.cn.

PMID: 33593833
PMCID: PMC8092886
DOI: 10.1128/AAC.02010-20

Abstract

Two novel ISCR1-associated dfr genes, dfrA42 and dfrA43, were identified from trimethoprim (TMP)-resistant Proteus strains and were shown to confer high level TMP resistance (MIC ≥ 1024 mg/L) when cloned into Escherichia coli These genes were hosted by complex class 1 integrons suggesting their potentials for dissemination. Analysis of enzymatic parameters and TMP affinity were performed, suggesting that the mechanism of TMP resistance for these novel DHFRs is the reduction of binding with TMP.

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Figures

**FIG 1**
Genetic structures of two novel *dfr* genes and phylogenetic analysis of DHFRs. (A) Genetic structures of complex class 1 integrons. Gray and black arrows, antibiotic resistance genes (*dfrA42* and *dfrA43*); white arrows, conserved genetic elements of complex class 1 integrons; accession numbers HQ386845 and HQ386844, respectively. (B) Phylogenetic analysis of DHFRs. Red boxes, DfrA42 and DfrA43. GenBank accession numbers are listed alongside protein names. Numbers at each node are bootstrap values. Bar, evolutionary distance.

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References

1. Then RL. 2004. Antimicrobial dihydrofolate reductase inhibitors—achievements and future options: review. J Chemother 16:3–12. 10.1179/joc.2004.16.1.3. - DOI - PubMed
1. Huovinen P, Sundström L, Swedberg G, Sköld O. 1995. Trimethoprim and sulfonamide resistance. Antimicrob Agents Chemother 39:279–289. 10.1128/aac.39.2.279. - DOI - PMC - PubMed
1. Sköld O. 2001. Resistance to trimethoprim and sulfonamides. Vet Res 32:261–273. 10.1051/vetres:2001123. - DOI - PubMed
1. Wrobel A, Arciszewska K, Maliszewski D, Drozdowska D. 2020. Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors. J Antibiot (Tokyo) 73:5–27. 10.1038/s41429-019-0240-6. - DOI - PMC - PubMed
1. Kranz J, Schmidt S, Lebert C, Schneidewind L, Mandraka F, Kunze M, Helbig S, Vahlensieck W, Naber K, Schmiemann G, Wagenlehner FM. 2018. The 2017 update of the German clinical guideline on epidemiology, diagnostics, therapy, prevention, and management of uncomplicated urinary tract infections in adult patients. Part II: therapy and prevention. Urol Int 100:271–278. 10.1159/000487645. - DOI - PubMed

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[1] Then RL. 2004. Antimicrobial dihydrofolate reductase inhibitors—achievements and future options: review. J Chemother 16:3–12. 10.1179/joc.2004.16.1.3. - DOI - PubMed

[2] Then RL. 2004. Antimicrobial dihydrofolate reductase inhibitors—achievements and future options: review. J Chemother 16:3–12. 10.1179/joc.2004.16.1.3. - DOI - PubMed

[3] Huovinen P, Sundström L, Swedberg G, Sköld O. 1995. Trimethoprim and sulfonamide resistance. Antimicrob Agents Chemother 39:279–289. 10.1128/aac.39.2.279. - DOI - PMC - PubMed

[4] Huovinen P, Sundström L, Swedberg G, Sköld O. 1995. Trimethoprim and sulfonamide resistance. Antimicrob Agents Chemother 39:279–289. 10.1128/aac.39.2.279. - DOI - PMC - PubMed

[5] Sköld O. 2001. Resistance to trimethoprim and sulfonamides. Vet Res 32:261–273. 10.1051/vetres:2001123. - DOI - PubMed

[6] Sköld O. 2001. Resistance to trimethoprim and sulfonamides. Vet Res 32:261–273. 10.1051/vetres:2001123. - DOI - PubMed

[7] Wrobel A, Arciszewska K, Maliszewski D, Drozdowska D. 2020. Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors. J Antibiot (Tokyo) 73:5–27. 10.1038/s41429-019-0240-6. - DOI - PMC - PubMed

[8] Wrobel A, Arciszewska K, Maliszewski D, Drozdowska D. 2020. Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors. J Antibiot (Tokyo) 73:5–27. 10.1038/s41429-019-0240-6. - DOI - PMC - PubMed

[9] Kranz J, Schmidt S, Lebert C, Schneidewind L, Mandraka F, Kunze M, Helbig S, Vahlensieck W, Naber K, Schmiemann G, Wagenlehner FM. 2018. The 2017 update of the German clinical guideline on epidemiology, diagnostics, therapy, prevention, and management of uncomplicated urinary tract infections in adult patients. Part II: therapy and prevention. Urol Int 100:271–278. 10.1159/000487645. - DOI - PubMed

[10] Kranz J, Schmidt S, Lebert C, Schneidewind L, Mandraka F, Kunze M, Helbig S, Vahlensieck W, Naber K, Schmiemann G, Wagenlehner FM. 2018. The 2017 update of the German clinical guideline on epidemiology, diagnostics, therapy, prevention, and management of uncomplicated urinary tract infections in adult patients. Part II: therapy and prevention. Urol Int 100:271–278. 10.1159/000487645. - DOI - PubMed

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Identification and characterization of two novel IS CR1-associated genes dfrA42 and dfrA43 encoding trimethoprim resistant dihydrofolate reductases

Affiliations

Identification and characterization of two novel IS CR1-associated genes dfrA42 and dfrA43 encoding trimethoprim resistant dihydrofolate reductases

Authors

Affiliations

Abstract

Figures

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