Mochizuki H, Yamada H, Oikawa Y, Murakami K, Ishiguro J, Kosuzume H, Aizawa N, Mochida E
Fuji Central Research Laboratory, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan.
Antimicrob Agents Chemother. 1988 Nov;32(11):1648-54. doi: 10.1128/AAC.32.11.1648.
The bactericidal activity of M14659 against Escherichia coli in low-iron environments was investigated and compared with that of ceftriaxone and ceftazidime. The bactericidal activity of M14659 against E. coli in Mueller-Hinton broth was enhanced 30- to 20,000-fold by addition of transferrin, which is an iron-binding protein, whereas the activity of ceftriaxone or ceftazidime was much less strongly affected. This enhancement by transferrin was completely inhibited by saturating the iron-binding capacity of transferrin with FeCl3. M14659 was taken up markedly into bacterial cells in the presence of transferrin, and its uptake was inhibited by the protonophore dinitrophenol, which inhibits active-transport systems coupled to an energized membrane such as the iron transport systems of E. coli. The bactericidal activity of M14659, which chelates Fe3+, was also enhanced in the presence of other iron-binding compounds such as lactoferrin and alpha,alpha'-dipyridyl or in iron-deficient Mueller-Hinton broth (Fe3+ concentration, less than 2 nM) supplemented with FeCl3 at 0.1 to 1.0 microM, but not in unsupplemented iron-deficient Mueller-Hinton broth. The E. coli used in this study was confirmed to derepress iron transport systems in the presence of transferrin, lactoferrin, and alpha,alpha'-dipyridyl and in the iron-deficient Mueller-Hinton broth supplemented with FeCl3 at 0 to 1.0 microM. M14659 also showed an excellent antibacterial activity in vitro against other gram-negative bacteria in the low-iron environments. These findings indicate that M14659 may be actively taken up with Fe3+ into bacterial cells, probably through the iron transport systems under conditions of low iron and, thus, kills bacteria effectively.
研究了M14659在低铁环境中对大肠杆菌的杀菌活性，并与头孢曲松和头孢他啶进行了比较。在穆勒-欣顿肉汤中，添加铁结合蛋白转铁蛋白可使M14659对大肠杆菌的杀菌活性提高30至20000倍，而头孢曲松或头孢他啶的活性受影响程度则小得多。用FeCl3使转铁蛋白的铁结合能力饱和后，转铁蛋白的这种增强作用被完全抑制。在有转铁蛋白存在的情况下，M14659可显著被细菌细胞摄取，其摄取受到质子载体二硝基苯酚的抑制，二硝基苯酚可抑制与能量化膜偶联的主动转运系统，如大肠杆菌的铁转运系统。螯合Fe3+的M14659的杀菌活性在存在其他铁结合化合物（如乳铁蛋白和α，α'-联吡啶）时，或在添加了0.1至1.0 microM FeCl3的缺铁穆勒-欣顿肉汤（Fe3+浓度小于2 nM）中也会增强，但在未添加的缺铁穆勒-欣顿肉汤中则不会。本研究中使用的大肠杆菌在存在转铁蛋白、乳铁蛋白和α，α'-联吡啶以及添加了0至1.0 microM FeCl3的缺铁穆勒-欣顿肉汤中被证实可解除对铁转运系统的抑制。M14659在体外对低铁环境中的其他革兰氏阴性菌也表现出优异的抗菌活性。这些发现表明，M14659可能在低铁条件下通过铁转运系统与Fe3+一起被主动摄取到细菌细胞中，从而有效杀死细菌。
