Department of Pathogen Biology, Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
J Bacteriol. 2019 Sep 20;201(20). doi: 10.1128/JB.00374-19. Print 2019 Oct 15.
Cyclopropane fatty acids (CFAs) are synthetized by the addition of a methylene group from -adenosyl-l-methionine across the carbon-carbon double bonds of unsaturated fatty acid chains of membrane phospholipids. This fatty acid cyclopropanation, catalyzed by the CFA synthase (CfaS) enzyme, occurs in many bacteria, including the human pathogen Although the cyclopropane modification was reported to play a key role in the adaptation in response to environmental stress, its role in remains unknown. In this study, we showed that HP0416 encodes a functional CfaS. The enzyme was demonstrated to be required for acid resistance, antibiotic resistance, intracellular survival and mouse gastric colonization, and cell membrane integrity. Moreover, the tool compound dioctylamine, which acts as a substrate mimic, directly inhibits the CfaS function of , resulting into sensitivity to acid stress, increased antibiotic susceptibility, and attenuated abilities to avoid macrophage killing and to colonize mouse stomachs. These results validate CfaS as a promising antibiotic target and provide new potentials for this recognized target in future anti- drug discovery efforts. The increasing prevalence of multidrug-resistant strains has created an urgent need for alternative therapeutic regimens that complement the current antibiotic treatment strategies for eradication; however, this is greatly hampered due to a lack of "druggable" targets. Although the CFAs are present in cytoplasmic membranes at high levels, their physiological role has not been established. In this report, deletion of the CFA synthase CfaS was shown to attenuate acid and drug resistance, immune escape, and gastric colonization of These findings were validated by inhibition of the CfaS activity with the tool compound dioctylamine. These studies identify this enzyme as an attractive target for further drug discovery efforts against .
环丙烷脂肪酸（CFAs）是通过将 - 腺苷基 -L- 蛋氨酸中的一个亚甲基基团添加到细胞膜磷脂的不饱和脂肪酸链的碳-碳双键上来合成的。这种脂肪酸环丙烷化作用由 CFA 合成酶（CfaS）酶催化，发生在许多细菌中，包括人类病原体 。尽管环丙烷修饰被报道在适应环境压力方面发挥关键作用，但在 中其作用尚不清楚。在这项研究中，我们表明 HP0416 编码一种功能性 CfaS。该酶被证明是耐酸、耐抗生素、细胞内存活和小鼠胃定植以及细胞膜完整性所必需的。此外，工具化合物二辛胺，作为底物类似物，直接抑制 的 CfaS 功能，导致对酸应激的敏感性增加、抗生素敏感性增加以及逃避巨噬细胞杀伤和定植小鼠胃的能力减弱。这些结果验证了 CfaS 作为有前途的抗生素靶标，并为未来抗药性药物发现工作提供了这一公认靶标的新潜力。多药耐药 菌株的日益流行迫切需要替代治疗方案来补充当前用于根除 的抗生素治疗策略；然而，由于缺乏“可成药”靶点，这一目标受到了极大的阻碍。尽管 CFAs 以高浓度存在于细胞质膜中，但它们的生理作用尚未确定。本报告显示，CfaS 的缺失削弱了 的耐酸和耐药物性、免疫逃避和胃定植。这些发现通过使用工具化合物二辛胺抑制 CfaS 活性得到了验证。这些研究将该酶确定为针对 的进一步药物发现努力的有吸引力的靶标。
