Antibacterials Research Unita and Medicinal Chemistry, Groton, Connecticut, USA.
Antimicrob Agents Chemother. 2013 Sep;57(9):4197-207. doi: 10.1128/AAC.00629-13. Epub 2013 Jun 17.
Multidrug resistance in Gram-negative bacteria has become so threatening to human health that new antibacterial platforms are desperately needed to combat these deadly infections. The concept of siderophore conjugation, which facilitates compound uptake across the outer membrane by hijacking bacterial iron acquisition systems, has received significant attention in recent years. While standard in vitro MIC and resistance frequency methods demonstrate that these compounds are potent, broad-spectrum antibacterial agents whose activity should not be threatened by unacceptably high spontaneous resistance rates, recapitulation of these results in animal models can prove unreliable, partially because of the differences in iron availability in these different methods. Here, we describe the characterization of MB-1, a novel siderophore-conjugated monobactam that demonstrates excellent in vitro activity against Pseudomonas aeruginosa when tested using standard assay conditions. Unfortunately, the in vitro findings did not correlate with the in vivo results we obtained, as multiple strains were not effectively treated by MB-1 despite having low MICs. To address this, we also describe the development of new in vitro assays that were predictive of efficacy in mouse models, and we provide evidence that competition with native siderophores could contribute to the recalcitrance of some P. aeruginosa isolates in vivo.
革兰氏阴性菌的多重耐药性对人类健康构成了如此严重的威胁，以至于急需新的抗菌平台来对抗这些致命感染。近年来，人们对铁载体共轭这一概念给予了极大的关注，该概念通过劫持细菌的铁获取系统，促进化合物穿过外膜被摄取。虽然标准的体外 MIC 和耐药频率方法表明这些化合物是有效的、广谱的抗菌剂，其活性不应受到不可接受的高自发耐药率的威胁，但在动物模型中重现这些结果可能并不可靠，部分原因是这些不同方法中铁的可用性存在差异。在这里，我们描述了一种新型铁载体共轭单环β-内酰胺抗生素 MB-1 的特性，当使用标准检测条件进行测试时，它对铜绿假单胞菌表现出极好的体外活性。不幸的是，体外发现与我们在体内获得的结果不相关，尽管 MB-1 的 MIC 较低，但仍有多种菌株未得到有效治疗。为了解决这个问题，我们还描述了新的体外检测方法的开发，这些方法可预测在小鼠模型中的疗效，并且我们提供了证据表明与天然铁载体的竞争可能导致一些铜绿假单胞菌分离株在体内的顽固。
