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. 2018 Jun 26;62(7):e00364-18. doi: 10.1128/AAC.00364-18

TABLE 1.

List of mutations associated with the folate biosynthesis pathway identified in endpoint isolates of TMP-SMX-evolved Nocardia strainsa

Strain Isolate MIC (mg/liter TMP-SMX) Mutation(s)
 Descriptionb
DHFR/FolA DHPS/FolP FolP2 FolE FtsH GpgS ThyA
ATCC 33727 2-4 >32-608 Ile99Thr Ser27Pro 1-bp deletion at position −64 position SNP at position −37, transcriptional regulator, TetR family; V560G sensory box/GGDEF family protein; d-alanyl–d-alanine carboxypeptidase/integral membrane efflux protein (position −88/−33); SNP at position +60, CAIB/BAIF family; 2-bp →CA (R209Q) at position 625, enoyl-CoA hydratase; 9 others
MDA0897 1-5 >32-608 Met30Arg SNP at position −16 Siderophore biosynthesis nonribosomal peptide synthetase modules at bacillibactin synthetase component F (I10849L); 13 others
MDA5529 2-5 >32-608 Phe26Ser Gly210Glu SNP at positions −65 and −12, GntR family; W31* sensor histidine kinase MtrB; R142M, enoyl-CoA hydratase; 5 others
MDA3349 (c) 1-4 16-304 Phe36Leu Val101Ala C6→7 (gene fusion) 2 others
MDA0897 2-1 16-304 Ile99Leu Phe26Cys Lys212Glu N98K, methionine ABC transporter; 5 others
MDA0897 2-3 16-304 Ile99Leu Phe26Cys Lys212Glu P99L and N98K, methionine ABC transporter; 3 others
ATCC 33727 1-4 16-304 Ile155Thr Phe26Cys Insertion at nucleotide 227 Δ12-bp sensory box/GGDEF protein; 2-bp →CA (R209Q) at position 625, enoyl-CoA hydratase; 5 others
ATCC 10905 1-1 16-304 Ile155Thr Phe26Cys Thr116Pro SNP at position −150 S269L, sensor histidine kinase MtrB; K53E transcriptional regulator, TetR family; S183A, PstB; 7 others
ATCC 10905 1-2 16-304 Ile155Thr Phe26Cys Thr116Pro SNP at position −150 S269L, sensor histidine kinase MtrB; 5 others
MDA3349 (c) 1-33 16-304 Phe36Leu C6→7 (gene fusion) Transcriptional regulator, MarR family, E90*; siderophore biosynthesis nonribosomal peptide synthetase modules at bacillibactin synthetase component F (A6732V); 2 others
MDA3349 (c) 1-38 16-304 Phe36Leu C6→7 (gene fusion) Transcriptional regulator, MarR family, E90*; siderophore biosynthesis nonribosomal peptide synthetase modules at bacillibactin synthetase component F (A6732V); 2 others
MDA3732 (c) 1-1 16-304 Phe36Leu C6→7 (gene fusion) TC→CA at position −63 P253T, transcriptional regulator, AraC family
ATCC 10905 2-1 16-304 Phe26Cys 2 others
ATCC 10905 2-2 16-304 Phe26Ser, Glu164Asp 6 others
MDA5529 1-4 16-304 Phe26Leu C6→5 R142M, enoyl-CoA hydratase; 4 others
ATCC 33727 1-2 16-304 Phe26Cys Insertion at nucleotide 227 Δ12-bp sensory box/GGDEF protein; 2-bp → CA (R209Q) at position 625, enoyl-CoA hydratase; 6 others
BAA2227 2-4 16-304 Phe13Ser Lys212Glu SNP at position −27, transcriptional regulator, AraC family; 7 others
MDA3139 2-1 16-304 Phe13Leu C6→7 (gene fusion) SNP at position −61, Glu215Gln +G at nucleotide 12, integral membrane protein (rhomboid family); L371P, methionine ABC transporter; SNP at position −175, enoyl-CoA hydratase; 14 others
MDA3139 2-3 16-304 Phe13Leu C6→7 (gene fusion) SNP at position −61, Glu215Gln Siderophore biosynthesis nonribosomal peptide synthetase modules at bacillibactin synthetase component F (F1011S); L371P, methionine ABC transporter; 15 others
MDA3349 (c) 1-31 16-304 Phe13Ser, Asp172Glu 12-bp deletion Asp770Asp SNP at position −34, integral membrane protein (rhomboid family); 1 other
MDA3397 2-3 16-304 Phe13Cys Arg243Cys Δ144-bp transcription repair-coupling factor; *210E transcriptional regulator, TetR family; 7 others
MDA3397 2-5 16-304 Phe13Cys Arg243Cys 4 others
MDA5529 2-1 16-304 Phe26Ser Gly210Glu W31* sensor histidine kinase MtrB; R142M, enoyl-CoA hydratase; 6 others
BAA2227 1-1 16-304 Ile112Thr d-Alanyl–d-alanine carboxypeptidase/integral membrane efflux protein (position −80/−41); F458Y, CAIB-BAIF family; 15 others
BAA2227 1-3 16-304 Ile112Thr Transcriptional regulator, MarR family, R136C; I36S, PstB; 13 others
MDA3349 (c) 2-18 16-304 C6→7 (gene fusion) Asp770Asp 1 other
MDA3349 (c) 2-69 16-304 I131T, SNP at position −53 8 others
MDA3139 1-1 8-152 Ile155Thr Phe13Ser Lys212Glu Transcriptional regulator, MarR family, at position −30; Δ1 bp at position 9, transcription repair-coupling factor; 12 others
MDA3139 1-5 8-152 Ile155Thr Phe13Ser Lys212Glu Asp473Gly Transcriptional regulator, MarR family, at position −30; Δ1 bp at position 9, transcription repair-coupling factor; 12 others
MDA0666 1-2 8-152 Ile30Thr Phe13Cys C5→6 P34A, transcriptional regulator, ArsR family; insertion at position 632 and L429P, sensory box/GGDEF family protein; 12 others
MDA0666 1-1 8-152 Ile30Thr Phe13Cys SNP at position −135 P34A, transcriptional regulator, ArsR family; insertion at position 632, sensory box/GGDEF family protein; 10 others
MDA3349 (c) 1-7 8-152 Phe36Leu C6→7 (gene fusion) 5 others
MDA3349 (c) 1-1 8-152 Phe36Leu C6→7 (gene fusion) 2 others
MDA3732 (c) 1-2 8-152 Phe36Leu C6→7 (gene fusion) TC→CA at position −63 P253T, transcriptional regulator, AraC family
BAA2227 2-2 8-152 Phe13Ser Lys212Glu SNP at position −27, transcriptional regulator, AraC family; 8 others
MDA5529 1-5 8-152 Phe26Leu C6→5 *798Trp R142M, enoyl-CoA hydratase; 3 others
MDA3349 (c) 2-110 8-152 Asp172Glu Asp770Asp SNP at positions −44 and −50, GntR family; 2 others
MDA3349 (c) 2-16 8-152 Asp172Glu Asp770Asp 3 others
MDA3349 (c) 2-93 8-152 Asp172Glu Asp770Asp 2 others
MDA3349 (c) 2-12 8-152 Asp172Glu Asp770Asp 1 other
MDA3349 (c) 2-89 8-152 Asp172Glu Asp770Asp 1 other
MDA3349 (c) 2-94 8-152 Asp172Glu Asp770Asp 1 other
MDA3349 (c) 2-103 8-152 Asp172Glu Asp770Asp 1 other
MDA3349 (c) 2-3 8-152 C6→5, Arg82Gln
MDA3349 (c) 2-13 8-152 C6→7 (gene fusion) Asp770Asp 1 other
MDA3349 (c) 2-106 8-152 C6→7 (gene fusion) Asp770Asp 2 others
MDA3732 (c) 2-1 8-152 Asp770Asp P253T, transcriptional regulator, AraC family; 2 others
MDA3732 (c) 2-2 8-152 Asp770Asp SNP at position −39, integral membrane protein (rhomboid family); P253T, transcriptional regulator, AraC family; 3 others
MDA3349 (c) 1-47 8-152 Δ2-bp transcription repair-coupling factor
MDA3349 (c) 1-48 4-76 C6→7 (gene fusion) 4 others
MDA3349 (c) 1-14 4-76 Arg262His 1 other
MDA3349 (c) 2-42 4-76 Arg82Gln Transcriptional regulator, MarR family, E73*; SNP at position −60, transcriptional regulator, ArsR family; T170P, transcriptional regulator, TetR family; 2 others
MDA3349 (c) 1-19 4-76 12-bp deletion Asp770Asp SNP at position −34, integral membrane protein (rhomboid family); R454C, sensor histidine kinase MtrB; 2 others
MDA3349 (c) 2-65 1-19 E84K, transcription repair-coupling factor
MDA3349 (c) 2-66 1-19 4 others
MDA3349 (c) 1-26 1-19 1 other
MDA3349 (c) 1-44 1-19 1 other
MDA3349 (c) 1-11 1-19 1 other
a

 Isolates are arranged in decreasing order of TMP-SMX MICs. MDA3349 isolates 1-47, 1-15, 1-43, 2-41, and 2-6 had MICs of 1-19 mg/liter TMP-SMX and had no mutations. Abbreviations: DHFR/FolA, dihydrofolate reductase; DHPS/FolP, dihydropteroate synthase; FolP2, dihydropteroate synthase homolog; FolE, GTP cyclohydrolase I; FtsH, cell division protein; GpgS, glucosyl-3-phosphoglycerate synthase; ThyA, thymidylate synthase; SNP, single nucleotide polymorphism. (c) represents Nocardia cyriacigeorgica strains. All other strains are Nocardia nova strains.

b

Mutations listed in this column are those that occur in genes not directly involved in the folate biosynthesis pathway but are seen in more than 1 strain, suggesting that they may be adaptive. If a gene is affected within multiple isolates of the same strain, it is listed as “other.” See Data Sets S1 and S2 in the supplemental material for complete details of all mutations observed in these isolates.