Pneumocystis carinii mutations associated with sulfa and sulfone prophylaxis failures in AIDS patients
Pneumocystis carinii mutations associated with sulfa and sulfone prophylaxis failures in AIDS patients
复制标题
DOI：
10.1097/00002030-199808000-00009
复制
发表时间：
1998-01-01
期刊：
影响因子：
3.8
通讯作者：
Meshnick, SR
中科院分区：
文献类型：
--
作者：
Kazanjian, P;Locke, AB;Meshnick, SR
背景：艾滋病患者预防卡氏肺囊虫肺炎（PCP）失败的情况时有发生，但尚未出现耐药的证据。目的：确定磺胺和砜类药物靶点的突变是否与使用含磺胺药物预防失败有关。方法：对1976 ~ 1997年诊断为PCP的27例患者（其中20例艾滋病患者）的磺胺和砜类靶点——卡氏双氢蝶呤合成酶（P. carinii dihydropteroate synthase， DHPS）的部分基因进行聚合酶链反应扩增和测序。27例患者中有7例（均为艾滋病患者）正在接受磺胺或砜类药物作为PCP的预防措施。结果：仅在两个氨基酸位置发现突变，并且在接受磺胺/砜预防的患者中更为常见。在接受磺胺/砜预防的艾滋病患者的7个分离株中，有5个（71%）观察到突变，而在未接受磺胺/砜预防的艾滋病患者的13个标本中，只有2个（15%）观察到突变（P = 0.022）。在7名未感染艾滋病毒的患者分离株中未发现突变，这些患者均未接受预防治疗。突变仅在1995-1997年获得的标本中观察到。结论：两个氨基酸位点的突变在磺胺/砜预防失败的艾滋病PCP患者中更为常见。根据与大肠杆菌DHPS晶体结构的同源性，这些氨基酸似乎直接参与底物和硫酸盐的结合。因此，该结果与卡氏杆菌DHPS突变可能是导致艾滋病患者磺胺/砜预防失败的原因一致。(C) 1998 Lippincott-Raven出版社。
Background: Failures of prophylaxis against Pneumocystis carinii pneumonia (PCP) in AIDS patients do occur, but no evidence for drug resistance has yet been presented.Objective: To determine whether mutations in the sulfa and sulfone drug target are associated with failure of prophylaxis using a sulfa-containing agent.Methods: Portions of the gene for P. carinii dihydropteroate synthase (DHPS), the sulfa and sulfone target, from 27 patients (20 of whom had AIDS) diagnosed with PCP between 1976 and 1997 were amplified using polymerase chain reaction and sequenced. Seven of the 27 patients (all of whom had AIDS) were receiving sulfa or sulfone drugs as prophylaxis for PCP.Results: Mutations were found at only two amino-acid positions and were significantly more common in patients who received sulfa/sulfone prophylaxis. Mutations were observed in five (71%) out of seven isolates from AIDS patients receiving sulfa/sulfone as prophylaxis compared with only two (15%) out of 13 specimens from AIDS patients who did not (P = 0.022). No mutations were seen in isolates from seven non-HIV-infected patients, none of whom were on prophylaxis. Mutations were only observed in specimens obtained in 1995-1997.Conclusions: Mutations in two amino-acid positions were significantly more common in AIDS patients with PCP who failed sulfa/sulfone prophylaxis. These amino acids appeared to be directly involved in both substrate and sulfa binding, based on homology to the Escherichia coli DHPS crystal structure. Thus, the results were consistent with the possibility that mutations in the P. carinii DHPS are responsible for some of the failures of sulfa/sulfone prophylaxis in AIDS patients. (C) 1998 Lippincott-Raven Publishers.