Ripoll-Rozada Jorge, García-Cazorla Yolanda, Getino María, Machón Cristina, Sanabria-Ríos David, de la Cruz Fernando, Cabezón Elena, Arechaga Ignacio
Departamento de Biología Molecular and Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Universidad de Cantabria-CSIC, Santander, Spain.
Inter American University of Puerto Rico-Metropolitan Campus, Faculty of Science and Technology, San Juan, Puerto Rico.
Mol Microbiol. 2016 Jun;100(5):912-21. doi: 10.1111/mmi.13359. Epub 2016 Mar 22.
Bacterial conjugation is the main mechanism responsible for the dissemination of antibiotic resistance genes. Hence, the search for specific conjugation inhibitors is paramount in the fight against the spread of these genes. In this pursuit, unsaturated fatty acids have been found to specifically inhibit bacterial conjugation. Despite the growing interest on these compounds, their mode of action and their specific target remain unknown. Here, we identified TrwD, a Type IV secretion traffic ATPase, as the molecular target for fatty acid-mediated inhibition of conjugation. Moreover, 2-alkynoic fatty acids, which are also potent inhibitors of bacterial conjugation, are also powerful inhibitors of the ATPase activity of TrwD. Characterization of the kinetic parameters of ATPase inhibition has led us to identify the catalytic mechanism by which fatty acids exert their activity. These results open a new avenue for the rational design of inhibitors of bacterial conjugation in the fight against the dissemination of antibiotic resistance genes.
细菌接合是抗生素耐药基因传播的主要机制。因此，寻找特异性接合抑制剂对于对抗这些基因的传播至关重要。在这一探索过程中，人们发现不饱和脂肪酸可特异性抑制细菌接合。尽管对这些化合物的兴趣与日俱增，但其作用方式和特定靶点仍不明确。在此，我们确定了IV型分泌转运ATP酶TrwD是脂肪酸介导的接合抑制作用的分子靶点。此外，同样作为细菌接合强效抑制剂的2-炔酸，也是TrwD ATP酶活性的强效抑制剂。对ATP酶抑制动力学参数的表征使我们确定了脂肪酸发挥其活性的催化机制。这些结果为合理设计细菌接合抑制剂以对抗抗生素耐药基因的传播开辟了一条新途径。
