Genther C S, Schoeny R S, Loper J C, Smith C C
Antimicrob Agents Chemother. 1977 Jul;12(1):84-92. doi: 10.1128/AAC.12.1.84.
Compounds that compete with folic acid (folic acid antagonists [FAAs]) become limited in their usefulness in the treatment of leukemia, malaria, and bacterial infections by the rapid development of resistance. Assays of the plasma levels of certain of these FAAs led to the observation, in about 25% of the determinations, that a higher density of growth of Streptococcus faecium var. durans (ATCC 8043) was obtained at an FAA concentration just below the completely inhibitory level than at one-half this concentration. This and other considerations suggested that FAAs may act not only as selective agents for resistant organisms but also as mutagens. Seven FAAs including amethopterin, pyrimethamine, trimethoprim, chlorguanide triazine, an experimental quinazoline, WR-158,122, and two experimental triazines, WR-99,210 and WR-38,839, were tested for mutagenicity in the Salmonella reversion assay developed by Ames et al. (1975). All were found to be negative for strains TA1535, TA1537, TA1538, TA98, and TA100, both with and without microsomal activation. These compounds were then tested as mutagens for three traits in the folic acid-requiring S. faecium. FAAs were shown to cause mutations to folic acid independence, rifampin resistance, and FAA resistance. It is postulated that the FAAs induce mutations by causing thymine deprivation in the folic acid-requiring host.
与叶酸竞争的化合物（叶酸拮抗剂[FAAs]）由于耐药性的迅速发展，在白血病、疟疾和细菌感染的治疗中其效用变得有限。对某些这类FAAs的血浆水平进行测定后发现，在约25%的测定中，粪肠球菌耐久变种（ATCC 8043）在略低于完全抑制水平的FAA浓度下生长密度高于该浓度一半时的生长密度。这一现象及其他因素表明，FAAs可能不仅作为耐药菌的选择剂，还作为诱变剂。在Ames等人（1975年）开发的沙门氏菌回复突变试验中，对包括氨甲蝶呤、乙胺嘧啶、甲氧苄啶、氯胍三嗪、一种实验性喹唑啉、WR - 158,122以及两种实验性三嗪WR - 99,210和WR - 38,839在内的七种FAAs进行了致突变性测试。结果发现，无论有无微粒体激活，这些化合物对TA1535、TA1537、TA1538、TA98和TA100菌株均呈阴性。然后，在需要叶酸的粪肠球菌中，对这些化合物作为三种性状的诱变剂进行了测试。结果表明，FAAs可导致对叶酸非依赖性、利福平耐药性和FAA耐药性的突变。据推测，FAAs通过使需要叶酸的宿主细胞胸腺嘧啶缺乏来诱导突变。
