Kazanjian P, Locke A B, Hossler P A, Lane B R, Bartlett M S, Smith J W, Cannon M, Meshnick S R
Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0378, USA.
AIDS. 1998 May 28;12(8):873-8. doi: 10.1097/00002030-199808000-00009.
Failures of prophylaxis against Pneumocystis carinii pneumonia (PCP) in AIDS patients do occur, but no evidence for drug resistance has yet been presented.
To determine whether mutations in the sulfa and sulfone drug target are associated with failure of prophylaxis using a sulfa-containing agent.
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.
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.
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.
艾滋病患者中预防卡氏肺孢子虫肺炎（PCP）确实会出现失败情况，但尚未有耐药性的证据。
确定磺胺类和砜类药物靶点的突变是否与使用含磺胺类药物预防失败相关。
采用聚合酶链反应扩增并测序1976年至1997年间诊断为PCP的27例患者（其中20例为艾滋病患者）的卡氏肺孢子虫二氢蝶酸合酶（DHPS）基因片段，该基因片段是磺胺类和砜类药物的靶点。27例患者中有7例（均为艾滋病患者）正在接受磺胺类或砜类药物预防PCP。
仅在两个氨基酸位置发现突变，且在接受磺胺类/砜类药物预防的患者中明显更常见。接受磺胺类/砜类药物预防的艾滋病患者的7株分离株中有5株（71%）出现突变，而未接受预防的艾滋病患者的13份标本中只有2株（15%）出现突变（P = 0.022）。7例非HIV感染患者的分离株中未发现突变，这些患者均未接受预防。突变仅在1995年至1997年获得的标本中观察到。
在接受磺胺类/砜类药物预防失败的PCP艾滋病患者中，两个氨基酸位置的突变明显更常见。基于与大肠杆菌DHPS晶体结构的同源性，这些氨基酸似乎直接参与底物和磺胺类药物的结合。因此，结果与卡氏肺孢子虫DHPS突变导致艾滋病患者中一些磺胺类/砜类药物预防失败的可能性一致。
