TRIMETHOPRIM RESISTANCE
TRIMETHOPRIM RESISTANCE
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DOI：
10.1128/aac.31.10.1451
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发表时间：
1987-10-01
影响因子：
4.9
通讯作者：
HUOVINEN, P
中科院分区：
文献类型：
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作者：
HUOVINEN, P
甲氧苄啶 (TMP) 是一种合成抗菌剂，属于二氨基嘧啶类化合物。这些药物抑制二氢叶酸还原酶 (DHFR; EC 1.5. 1.3)，这种酶在微生物和真核细胞中催化二氢叶酸还原为四氢叶酸 (14, 39)。二氨基嘧啶比叶酸更小，结构也与叶酸不同，这与氨基蝶呤和甲氨蝶呤不同，后者是结构与叶酸相似的 DHFR 抑制剂。氨基蝶呤和甲氨蝶呤可拮抗哺乳动物和微生物 DHFR，而二氨基嘧啶（例如 TMP）对抗微生物 DHFR 的活性比对抗哺乳动物 DHFR 的活性更高 (14)。 X 射线晶体学研究已经阐明了这种效力差异的原因。人们发现 TMP 非常适合大肠杆菌 DHFR 的底物结合位点，但不适用于哺乳动物 DHFR (55)。TMP 在体外对大多数需氧革兰氏阴性和革兰氏阳性细菌具有活性 (16)。已知对 TMP 具有内在抗性的细菌病原体比敏感的细菌病原体要少。 TMP 对某些类型的疟疾也具有活性 (18, 54)，并且与磺胺类药物联合使用可对抗卡氏肺孢子虫 (67)，但单独使用 TMP 对卡氏肺孢子虫的 DHFR 仅有非常弱的活性 (2)。 TMP于1962年首次在临床上与多粘菌素和磺胺类药物联合用于治疗变形杆菌败血症(62)。 TMP 和磺胺类药物之间发现的协同作用导致这些药物于 1968 年在英国和美国联合临床使用，并很快在全世界范围内使用 (17)。 TMP-磺酰胺组合可有效治疗多种不同的感染 (67)。由于磺胺类药物引起的副作用以及与单独使用TMP治疗泌尿道和呼吸道感染所获得的临床结果相当(5,13,47,50,51)，临床上也单独使用TMP。 TMP 首次于 1972 年在芬兰用于预防尿路感染 (47)，并于 1979 年在其他欧洲国家和美国 (50)。随着TMP的广泛使用，TMP耐药细菌病原体已成为一个重要的临床问题。本次小型综述的目的是回顾细菌中的 TMP 耐药性，考虑抑制 TMP 耐药性的机制、传播和方法。
Trimethoprim (TMP) is a synthetic antibacterial agent that belongs to a group of compounds called diaminopyrimidines. These agents inhibit dihydrofolate reductase (DHFR; EC 1.5. 1.3), an enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate in microbial and eucaryotic cells (14, 39). The diaminopyrimidines are smaller than and struc-turally unlike folate, incontrast to aminopterin and methotrexate, which are DHFR inhibitors that are structur-ally similar to folate. Aminopterin and methotrexate antag-onize both mammalian and microbial DHFR, whereas diami-nopyrimidines such as TMP are more active against microbial DHFR than against mammalian DHFR (14). The reason for this difference in potency has been eludicated by X-ray crystallography studies. TMP was found to fit well to the substrate-binding site of Escherichia coli DHFR but not mammalian DHFR (55).TMP is active in vitro against most aerobic gram-negative and gram-positive bacteria (16). Bacterial pathogens known to be intrinsically resistant to TMP are fewer than suscepti-ble ones. TMP is also active against certain types of malaria (18, 54) and, in combination with sulfonamides, against Pneumocystis carinii (67), although TMP alone has only very weak activity against the DHFR of P. carinii (2). TMP was first used clinically in the treatment of Proteus septicemia in combination with polymyxin and sulfonamides in 1962 (62). Synergy found between TMP and sulfonamides led to the clinical use of these drugs in combination in the United Kingdom and the United States in 1968 and worldwide soon after (17). A TMP-sulfonamide combination has been efficacious in the treatment of a variety of different infections (67). Because of side effects caused by sulfonamides and clinical outcome equivalent to that obtained with TMP alone in the treatment of urinary and respiratory tract infections (5, 13, 47, 50, 51), TMP has also been used clinically alone. TMP alone was first used for the prophy-laxis of urinary tract infections in Finland in 1972 (47) and in other European countries and the United States in 1979 (50). With the widespread use of TMP, TMP-resistant bacterial pathogens have emerged as a significant clinical problem. The purpose of this minireview is to review TMP resistance in bacteria, considering mechanisms, spread, and ap-proaches to the suppression of TMP resistance.