Department of Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Infect Genet Evol. 2013 Oct;19:1-6. doi: 10.1016/j.meegid.2013.06.008. Epub 2013 Jun 14.
It has been widely accepted, that pyrazinamide (PZA) resistance in Mycobacterium tuberculosis is correlated with mutations in the pncA gene. But since years researchers have been puzzled by the fact that up to 30% of PZA resistant strains do not show any correlation between PZA resistance and mutations in the pncA gene, and thus may vary with geographic area. The objective of the study was to investigate the correlation between PZA susceptibility and mutations in pncA gene in M. tuberculosis isolates from individuals living in a highly endemic area. Therefore we analyzed drug resistant and multidrug resistant (MDR) isolates from patients in Rio de Janeiro, Brazil. From a total of 97 clinical isolates of M. tuberculosis 35 were identified as PZA resistant, 24/35 strains did not show PZase activity and 15/24 (62.5%) strains possess mutation in the pncA gene. This is a low correlation between PZA resistance and PZase activity (68.6%) and even lower correlation between PZA resistance and the presence of mutation in pncA gene (45.7%). Most of the mutations found were conserved near the active site or metal binding site of PZase. The 146A>C mutation was found both in PZA resistant and susceptible isolates, suggesting that this mutation may not fully associated with PZA resistance. Of the mutations found, three have not been previously described. The insertions 192-193 TCCTCGTC and 388-389 AGGTCGATG, although found before, here was found to be a short tandem repeat and in one strain, insertion of the IS6110 was observed 55nt upstream of the gene. All PZA resistant isolates had no mutation in the gene coding ribosomal protein S1 (rpsA), which has recently been proposed as alternate target for pyrazinoic acid (POA). The results show a low association of PZA resistance and pncA gene mutations in a selected patient group from an highly endemic area. Our findings point out that the phenotypic susceptibility testing remains important for the detection of PZA-resistant M. tuberculosis.
吡嗪酰胺（PZA）耐药与结核分枝杆菌 pncA 基因突变广泛相关。然而，多年来，研究人员一直对以下事实感到困惑：高达 30%的 PZA 耐药株与 pncA 基因突变之间没有任何相关性，并且可能因地理位置而异。本研究旨在调查来自高度流行地区个体的结核分枝杆菌分离株中 PZA 敏感性与 pncA 基因突变之间的相关性。因此，我们分析了来自巴西里约热内卢的耐多药（MDR）患者的耐药和 MDR 分离株。从总共 97 株结核分枝杆菌临床分离株中，有 35 株被鉴定为 PZA 耐药，35 株中 24 株无 PZase 活性，24 株中有 15 株（62.5%）携带 pncA 基因突变。这表明 PZA 耐药与 PZase 活性之间的相关性较低（68.6%），与 pncA 基因突变之间的相关性甚至更低（45.7%）。大多数发现的突变位于 PZase 的活性位点或金属结合位点附近。146A>C 突变在 PZA 耐药和敏感分离株中均被发现，表明该突变可能不完全与 PZA 耐药相关。在所发现的突变中，有 3 个以前未被描述过。插入 192-193TCCTCGTC 和 388-389AGGTCGATG，虽然以前发现过，但这里发现是一个短串联重复，在一株菌中，插入的 IS6110 位于基因上游 55nt。所有 PZA 耐药分离株在核糖体蛋白 S1（rpsA）基因中均无突变，最近该基因被提议为吡嗪酸（POA）的替代靶标。结果表明，在来自高度流行地区的选定患者群体中，PZA 耐药性与 pncA 基因突变相关性较低。我们的研究结果表明，表型药敏试验对于检测耐 PZA 的结核分枝杆菌仍然很重要。
