Thr202Ala in thyA is a marker for the Latin American Mediterranean lineage of the Mycobacterium tuberculosis complex rather than para-aminosalicylic acid resistance.
Single nucleotide polymorphisms (SNPs) involved in the development of resistance represent powerful markers for the rapid detection of first- and second-line resistance in clinical Mycobacterium tuberculosis complex (MTBC) isolates. However, the association between particular mutations and phenotypic resistance is not always clear-cut, and phylogenetic SNPs have been misclassified as resistance markers in the past. In the present study, we investigated the utility of a specific polymorphism in thyA (Thr202Ala) as a marker for resistance to para-aminosalicyclic acid (PAS). Sixty-three PAS-susceptible MTBC strains comprising all major phylogenetic lineages, reference strain H37Rv, and 135 multidrug-resistant (MDR) strains from Germany (comprising 8 PAS-resistant isolates) were investigated for the presence of Thr202Ala. In both strain collections, the Thr202Ala SNP was found exclusively in strains of the Latin American Mediterranean (LAM) lineage irrespective of PAS resistance. Furthermore, PAS MICs (0.5 mg/liter) for selected LAM strains (all containing the SNP) and non-LAM strains (not containing the SNP), as well as the results of growth curve analyses performed in liquid 7H9 medium in the presence of increasing PAS concentrations (0 to 2.0 mg/liter), were identical. In conclusion, our data demonstrate that the Thr202Ala polymorphism in thyA is not a valid marker for PAS resistance but, instead, represents a phylogenetic marker for the LAM lineage of the M. tuberculosis complex. These findings challenge some of the previous understanding of PAS resistance and, as a consequence, warrant further in-depth investigations of the genetic variation in PAS-resistant clinical isolates and spontaneous mutants.
Feuerriegel
Silke
S
Molecular Mycobacteriology, Research Center Borstel, Parkallee 1, Borstel, Germany.
Köser
Claudio
C
Trübe
Leona
L
Archer
John
J
Rüsch Gerdes
Sabine
S
Richter
Elvira
E
Niemann
Stefan
S
D010131:Aminosalicylic Acid / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D016680:Genome, Bacterial / Q000235:genetics; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D010131:Aminosalicylic Acid
J Clin Microbiol. 2009 Jan;47(1):223-6
19020060
J Clin Microbiol. 2008 Aug;46(8):2692-9
18550737
Zhonghua Jie He He Hu Xi Za Zhi. 2007 Sep;30(9):683-5
18070553
Genome Biol. 2004;5(2):R12
14759262
J Clin Microbiol. 1997 Apr;35(4):907-14
9157152
Mol Microbiol. 2004 Jul;53(1):275-82
15225321
J Mol Biol. 1990 Oct 5;215(3):403-10
2231712
J Clin Microbiol. 1993 Feb;31(2):406-9
8381814
J Clin Microbiol. 2007 Mar;45(3):691-7
17192416
Antimicrob Agents Chemother. 2009 May;53(5):2100-9
19237648
Science. 2002 Mar 15;295(5562):2042-6
11896268
PLoS One. 2007 Nov 07;2(11):e1126
17987113
J Clin Microbiol. 2006 Dec;44(12):4498-510
17005759
PLoS One. 2009 Nov 05;4(11):e7778
19890396
J Antimicrob Chemother. 2010 Jul;65(7):1359-67
20427375
N Engl J Med. 2003 Jan 9;348(2):119-28
12519922
Emerg Infect Dis. 2008 Jun;14(6):992-3
18551748
Nucleic Acids Res. 2010 Jul;38(Web Server issue):W326-31
20457747