Corey Brendan W, Thompson Mitchell G, Hittle Lauren E, Jacobs Anna C, Asafo-Adjei Edward A, Huggins William M, Melander Roberta J, Melander Christian, Ernst Robert K, Zurawski Daniel V
Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research , Silver Spring, Maryland 20910, United States.
Department of Microbial Pathogenesis, University of Maryland School of Dentistry , Baltimore, Maryland 21201, United States.
ACS Infect Dis. 2017 Jan 13;3(1):62-71. doi: 10.1021/acsinfecdis.6b00133. Epub 2016 Nov 3.
Acinetobacter baumannii are Gram-negative bacilli that pose a constant threat to susceptible patients because of increased resistance to multiple antibiotics and persistence in the hospital environment. After genome analysis, we discovered that A. baumannii harbors genes that share homology to an enzymatic pathway that elongates long-chain fatty acids (LCFA) in fungi. Previously, 1,2,4-triazolidine-3-thiones (T-3-Ts) were shown to inhibit hyphae production in fungi, and this same LCFA elongation pathway was implicated as the possible target. Therefore, we investigated if T-3-Ts also have activity against multidrug-resistant A. baumannii. Surprisingly, all of the clinical isolates of A. baumannii that were tested have susceptibility to ECC145 and ECC188 with MIC values of 8.0 μg/mL. In contrast, reference strains and clinical isolates of other common nosocomial bacteria that lack the LCFA pathway also lacked susceptibility. Time-kill experiments revealed that both ECC145 and ECC188 have a bacteriostatic effect against A. baumannii. Mass spectrometry analysis suggested that exposure to T-3-Ts resulted in less LCFA production. Supplementation of media with either 0.02% w/v oleic or linoleic acid abrogated the bacteriostatic effect of the compounds, which again implicated LCFA elongation as the target. Our results suggest these molecules could be a promising start to further exploit what appears to be an important aspect of A. baumannii membrane function and integrity.
鲍曼不动杆菌是革兰氏阴性杆菌，由于对多种抗生素的耐药性增加以及在医院环境中的持久性，对易感患者构成持续威胁。经过基因组分析，我们发现鲍曼不动杆菌含有与真菌中延长长链脂肪酸（LCFA）的酶促途径具有同源性的基因。此前，1,2,4-三唑烷-3-硫酮（T-3-Ts）已被证明可抑制真菌中的菌丝产生，并且这一相同的LCFA延长途径被认为是可能的靶点。因此，我们研究了T-3-Ts对多重耐药鲍曼不动杆菌是否也有活性。令人惊讶的是，所有测试的鲍曼不动杆菌临床分离株对ECC145和ECC188敏感，MIC值为8.0μg/mL。相比之下，缺乏LCFA途径的其他常见医院细菌的参考菌株和临床分离株也不敏感。时间杀灭实验表明，ECC145和ECC188对鲍曼不动杆菌均有抑菌作用。质谱分析表明，暴露于T-3-Ts会导致LCFA产量降低。在培养基中添加0.02% w/v的油酸或亚油酸可消除这些化合物的抑菌作用，这再次表明LCFA延长是靶点。我们的结果表明，这些分子可能是一个有前景的开端，可进一步探索鲍曼不动杆菌膜功能和完整性这一重要方面。
