Characterization of Fosfomycin and Nitrofurantoin Resistance Mechanisms in Escherichia coli Isolated in Clinical Urine Samples
Abstract
:1. Introduction
2. Methods
2.1. Bacterial Isolates
2.2. Carbohydrate Utilization Test
2.3. PCR Amplification
2.4. Nucleotide Sequencing
3. Results
3.1. Fosfomycin Resistance
3.2. Nitrofurantoin Resistance
4. Discussion
4.1. Mechanisms of Resistance to Fosfomycin in E. coli
4.1.1. Modification or Overexpression of the Target (MurA)
4.1.2. Permeability Reduction
4.1.3. Enzymatic Modification of Fosfomycin
4.2. Mechanisms of Resistance to Nitrofurantoin in E. coli
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Gene | Forward Primer | Reverse Primer | Amplicon Size (bp) | Reference |
---|---|---|---|---|
murA | 5′-AAACAGCAGACGGTCTATGG-3′ | 5′-CCATGAGTTTATCGACAGAACG-3′ | 1542 | [9] |
glpT | 5′-GCGAGTCGCGAGTTTTCATTG-3′ | 5′-GGCAAATATCCACTGGCACC-3′ | 1785 | |
uhpT | 5′-TTTTTGAACGCCCAGACACC-3′ | 5′-AGTCAGGGGCTATTTGATGG-3′ | 1667 | |
uhpA | 5′-GATCGCGGTGTTTTTTCAG-3′ | 5′-GATACTCCACAGGCAAAACC-3′ | 771 | |
ptsI | 5′-GAAAGCGGTTGAACATCTGG-3′ | 5′-TCCTTCTTGTCGTCGGAAAC-3′ | 1908 | |
cyaA1 | 5′-AACCAGGCGCGAAAAGTGG-3′ | 5′-TGATGGCTGATGATCGACTC-3′ | 1559 | [9] This study |
cyaA2 | 5′-AAAGCTCAGCCGTGAACGC-3′ | 5′-ACCTTCTGGGATTTGCTGG-3′ | 1648 | |
nfsA | 5′-ATTTTCTCGGCCAGAAGTGC-3′ | 5′-AGAATTTCAACCAGGTGACC-3′ | 1036 | [5] |
nfsB | 5′-CTTCGCGATCTGATCAACG-3′ | 5′-CAACAGCAGCCTATGATGAC-3′ | 923 | |
ribE | 5′-AAGGGAAGCAGCGCACGAA-3′ | 5′-GGACAACTGCCAGGAGTAGA-3′ | 634 | This study |
fosA3 | 5′-GCGTCAAGCCTGGCATTT-3′ | 5′-GCCGTCAGGGTCGAGAAA-3′ | 282 | [10] |
fosA4 | 5′-CTGGCGTTTTATCAGCGGTT-3′ | 5′-CTTCGCTGCGGTTGTCTTT-3′ | 230 | [11] |
fosA5 | 5′-TATTAGCGAAGCCGATTTTGCT-3′ | 5′-CCCCTTATACGGCTGCTCG-3′ | 177 | |
fosA6 | 5′-GCTACGGTTCAGCTTCCAGA-3′ | 5′-CGAGCGTGGCGTTTTATCAG-3′ | 242 | This study |
fosC2 | 5′-CGTTCCGTGGAGTTCTATAC-3′ | 5′-CTTGATAGGGTTTAGACTTC-3′ | 334 | [8] |
oqxA | 5′-GACAGCGTCGCACAGAATG-3′ | 5′-GGAGACGAGGTTGGTATGGA-3′ | 339 | [12] |
oqxB | 5′-CGAAGAAAGACCTCCCTACCC-3′ | 5′-CGCCGCCAATGAGATACA-3′ | 240 |
Strain | Fosfomycin Disk 1 | Clinical Category 2 | Fosfomycin Disk Plus PPF 3 | G3P 4 | G6P 5 | Amino Acid Substitutions in | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
MurA | GlpT | UhpT | UhpA | PtsI | CyaA | ||||||
11 | 6 | R | 6 | + | − | None | Leu297Phe Glu443Gln Gln444Glu Glu448Lys | Not detected | Not detected | Arg367Lys | Asn142Ser Ala349Glu Ser352Thr Ser356Leu Gly359Glu Glu362Asp |
17 | 6 | R | 6 | + | − | None | Glu448Lys | Glu350Gln | Not detected | Val25Ile Arg367Lys | Asn142Ser Asp837Glu Thr840Ala |
26 | 12 | R | 12 | + | − a | None | Gly84Asp Glu448Lys | Not detected | None | Arg367Lys | Asn142Ser Ala349Glu Ser356Leu Gly359Glu Glu362Asp Ala363Ser Asp837Glu Thr840Ala |
66 | 6 | R | 13 | + | − | None | Glu448Lys | Glu350Gln | Not detected | Val25Ile Arg367Lys | Asn142Ser Asp837Glu Thr840Ala |
302 | 29 | S | 30 | + | + | None | Glu448Lys | None | None | Arg367Lys | Asn142Ser Gly222Ser |
334 | 31 | S | 32 | + | + | None | Glu448Lys | None | None | Arg367Lys | Asn142Ser |
381 | 6 | R | 6 | + | − | None | Glu448Lys | Glu350Gln | Not detected | Val25Ile Arg367Lys | Asn142Ser Asp837Glu Thr840Ala |
387 | 6 | R | 6 | + | − | None | Glu448Lys | Glu350Gln | Not detected | Val25Ile Arg367Lys | Asn142Ser Asp837Glu Thr840Ala |
462 | 12 | R | 13 | + | − | None | Glu448Lys | Glu350Gln | Not detected | Val25Ile Arg367Lys | Asn142Ser Asp837Glu Thr840Ala |
632 | 6 | R | 6 | + | − | None | Leu297Phe Glu443Gln Gln444Glu Glu448Lys | Glu350Gln | Not detected | Arg367Lys | Asn142Ser Ala349Glu Ser352Thr Ser356Leu Gly359Glu Glu362Asp Ala363Gly |
751 | 30 | S | 32 | + | + | None | Ala16Thr Glu448Lys | None | Arg46Cys | Ala306Thr Arg367Lys | Asn142Ser Ala349Glu Ser356Leu Gly359Glu Glu362Asp Asp837Glu Thr840Ala |
752 | 11 | R | 11 | + | − | None | Pro212Leu Glu448Lys | Glu350Gln | Not detected | Val25Ile Arg367Lys | Asn142Ser Asp837Glu Thr840Ala |
757 | 6 | R | 6 | + | − a | None | Leu297Phe Glu443Gln Gln444Glu Glu448Lys | None | Not detected | Arg367Lys | Asn142Ser Ala349Glu Ser352Thr Ser356Leu Gly359Glu Glu362Asp |
776 | 12 | R | 12 | + | − a | None | Glu448Lys | Glu350Gln | Not detected | Val25Ile Arg367Lys | Asn142Ser Asp837Glu Thr840Ala |
789 | 6 | R | 6 | + | − | Leu370Ile | Leu297Phe Glu443Gln Gln444Glu Glu448Lys | Glu350Gln | Not detected | Arg367Lys | Asn142Ser Ala349Glu Ser352Thr Ser356Leu Gly359Glu Glu362Asp |
792 | 6 | R | 6 | + | − | None | Glu448Lys | Glu350Gln | Not detected | Val25Ile Arg367Lys | Asn142Ser Asp837Glu Thr840Ala |
795 | 6 | R | 6 | + | − | None | Leu297Phe Glu443Gln Gln444Glu Glu448Lys | Glu350Gln | Not detected | Arg367Lys | Asn142Ser Ala349Glu Ser352Thr Ser356Leu Gly359Glu Glu362Asp |
797 | 20 | S | 21 | + | + | None | Ala16Thr Leu373Arg Glu448Lys | None | Arg46Cys | Ala306Thr Arg367Lys | Asn142Ser Ala349Glu Ser356Leu Gly359Glu Glu362Asp Asp837Glu Thr840Ala |
799 | 6 | R | 7 | + | − | None | Leu297Phe Glu443Gln Gln444Glu Glu448Lys | None | Not detected | Arg367Lys | Asn142Ser Ala349Glu Ser352Thr Ser356Leu Gly359Glu Glu362Asp |
802 | 30 | S | 30 | + | + | None | Phe133Cys Gly135Trp Ala197Val Glu448Lys | None | None | Arg367Lys | Asn142Ser |
809 | 6 | R | 6 | + | − | Leu370Ile | Leu297Phe Glu443Gln Gln444Glu Glu448Lys | Glu350Gln | Not detected | Arg367Lys | Asn142Ser Ala349Glu Ser352Thr Ser356Leu Gly359Glu Glu362Asp |
853 | 6 | R | 8 | + | − | Leu370Ile | Leu297Phe Glu443Gln Gln444Glu Glu448Lys | Glu350Gln | Not detected | Arg367Lys | Asn142Ser Ala349Glu Ser352Thr Ser356Leu Gly359Glu Glu362Asp |
854 | 6 | R | 6 | + | − | None | Glu448Lys | None | Not detected | Arg367Lys | Asn142Ser |
860 | 6 | R | 7 | + | − | None | Met52Leu Leu297Phe Glu443Gln Gln444Glu Glu448Lys | None | Not detected | Arg367Lys | Asn142Ser Ala349Glu Ser352Thr Ser356Leu Gly359Glu Glu362Asp |
871 | 6 | R | 14 | + | − a | None | Leu297Phe Glu443Gln Gln444Glu Glu448Lys | Glu350Gln | Not detected | Arg367Lys | Asn142Ser Ala349Glu Ser352Thr Ser356Leu Gly359Glu Glu362Asp Ala363Gly |
872 | 35 | S | 35 | + | + | None | Glu448Lys | None | None | Arg367Lys | Asn142Ser Asp837Glu Thr840Ala |
883 | 11 | R | 12 | + | − | None | Glu448Lys | Glu350Gln | Not detected | Val25Ile Arg367Lys | Asn142Ser Asp837Glu Thr840Ala |
891 | 11 | R | 11 | + | − | None | Glu448Lys | Glu350Gln | Not detected | Val25Ile Arg367Lys | Asn142Ser Asp837Glu Thr840Ala |
892 | 21 | S | 21 | + | + | None | Glu448Lys | None | None | Arg367Lys | Asn142Ser |
Strain | Nitrofurantoin Disk 1 | Clinical Category 2 | Amino Acid Substitutions in | ||
---|---|---|---|---|---|
NfsA | NfsB | RibE | |||
11 | 11 | R | Ile117Thr Gly126Arg Lys141Glu Gln147Arg Gly187Asp | Truncated at Glu54 | None |
17 | 27 | S | Ile117Thr Lys141Glu Gly187Asp | Gly66Asp Val93Ala Ala174Glu | None |
26 | 24 | S | Ile117Thr Lys141Glu Gly187Asp | Gly66Asp Val93Ala Ala174Glu | None |
66 | 14 | R | Ile117Thr Lys141Glu Gly187Asp | Gly66Asp Val93Ala Ala174Glu Arg207His | None |
302 | 14 | R | None | Gly66Asp Met75Ile Val93Ala Ala174Glu Arg207His | None |
334 | 15 | I | Gln67Leu | Gly66Asp Met75Ile Val93Ala Arg107Cys | Pro55His |
381 | 25 | S | Ile117Thr Lys141Glu Gly187Asp | Gly66Asp Val93Ala Ala174Glu | None |
387 | 21 | S | Ile117Thr Lys141Glu Gly187Asp | Gly66Asp Val93Ala Ala174Glu | None |
462 | 14 | R | Cys80Arg Ile117Thr Lys141Glu Gly187Asp | Gly66Asp Val93Ala Ala174Glu Gly192Ser | None |
632 | 20 | S | Glu58Asp Ile117Thr Lys141Glu Gln147Arg Gly187Asp | Val93Ala | None |
751 | 14 | R | Ile117Thr Lys141Glu Gly187Asp Arg203Cys | Gly66Asp Val93Ala Ala174Glu | Val51Ile |
752 | 22 | S | Ile117Thr Lys141Glu Gly187Asp | Gly66Asp Val93Ala Ala174Glu | None |
757 | 16 | I | Glu58Asp Truncated at Gln67 | Val93Ala Lys122Arg | None |
776 | 19 | S | Ile117Thr Lys141Glu Gly187Asp | Gly66Asp Val93Ala Ala174Glu | None |
789 | 24 | S | Glu58Asp Ile117Thr Lys141Glu Gln147Arg Gly187Asp | Val93Ala | None |
792 | 25 | S | Ile117Thr Lys141Glu Gly187Asp | Gly66Asp Val93Ala Ala174Glu | None |
795 | 16 | I | His11Tyr Glu58Asp Ile117Thr Lys141Glu Gln147Arg Gly187Asp | Val93Ala | None |
797 | 12 | R | Ile117Thr Lys141Glu Gly154Glu Gly187Asp | Leu22Ile Gly66Asp Val93Ala Ala174Glu | Val51Ile |
799 | 13 | R | Ile117Thr Lys141Glu Gln147Arg Gly187Asp | Val93Ala | None |
802 | 12 | R | Truncated at Gln147 | Met75Ile Val93Ala | None |
809 | 28 | S | Glu58Asp Ile117Thr Lys141Glu Gln147Arg Gly187Asp | Val93Ala | None |
853 | 20 | S | Glu58Asp Ile117Thr Lys141Glu Gln147Arg Gly187Asp | Val93Ala | None |
854 | 16 | I | None | Gly66Asp Met75Ile Val93Ala | None |
860 | 20 | S | Ile117Thr Lys141Glu Gln147Arg Gly187Asp | Val93Ala | None |
871 | 24 | S | Glu58Asp Ile117Thr Lys141Glu Gln147Arg Gly187Asp | Val93Ala | None |
872 | 15 | I | Asp19Asn Ser33Arg Ile117Thr Lys141Glu Gly187Asp | Gln44His Gly66Asp Val93Ala Ala174Glu | None |
883 | 13 | R | Ile117Thr Lys141Glu Gly187Asp | Gly66Asp Phe84Ser Val93Ala Ala174Glu | None |
891 | 23 | S | Ile117Thr Lys141Glu Gly187Asp | Gly66Asp Val93Ala Ala174Glu | None |
892 | 10 | R | None | Gly66Asp Met75Ile Val93Ala | None |
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Sorlozano-Puerto, A.; Lopez-Machado, I.; Albertuz-Crespo, M.; Martinez-Gonzalez, L.J.; Gutierrez-Fernandez, J. Characterization of Fosfomycin and Nitrofurantoin Resistance Mechanisms in Escherichia coli Isolated in Clinical Urine Samples. Antibiotics 2020, 9, 534. https://doi.org/10.3390/antibiotics9090534
Sorlozano-Puerto A, Lopez-Machado I, Albertuz-Crespo M, Martinez-Gonzalez LJ, Gutierrez-Fernandez J. Characterization of Fosfomycin and Nitrofurantoin Resistance Mechanisms in Escherichia coli Isolated in Clinical Urine Samples. Antibiotics. 2020; 9(9):534. https://doi.org/10.3390/antibiotics9090534
Chicago/Turabian StyleSorlozano-Puerto, Antonio, Isaac Lopez-Machado, Maria Albertuz-Crespo, Luis Javier Martinez-Gonzalez, and Jose Gutierrez-Fernandez. 2020. "Characterization of Fosfomycin and Nitrofurantoin Resistance Mechanisms in Escherichia coli Isolated in Clinical Urine Samples" Antibiotics 9, no. 9: 534. https://doi.org/10.3390/antibiotics9090534