Crystal Structures of the Acinetobacter baumannii Macrolide Phosphotransferase E

IF 4 2区 医学 Q2 CHEMISTRY, MEDICINAL
Qianqian Qi, Linghan Kuang, Jing Liao, Xiang Wang, Yanxia Zhou, Li Guo, Yongmei Jiang
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Abstract

Acinetobacter baumannii (A. baumannii) challenges clinical infection treatment due to its resistance to various antibiotics. Multiple resistance genes in the core genome or mobile elements contribute to multidrug resistance in A. baumannii. Macrolide phosphotransferase gene mphE has been identified in A. baumannii, which is particularly relevant to macrolide antibiotics. Here, we determined the structure of MphE protein in three states: the apo state, the complex state with erythromycin and guanosine triphosphate (GTP), and the complex state with azithromycin and guanosine. Interestingly, GTP and two magnesium ions were observed in the erythromycin-bound MphE complex. This structure captured the active state of MphE, in which the magnesium ions stabilized the active site and assisted the transfer of phosphoryl groups. Based on these structures, we verified that the conserved residues Asp29, Asp194, His199, and Asp213 play an important role in the catalytic phosphorylation of MphE leading to drug resistance. Our work helps to understand the molecular basis of drug resistance and provides reference targets for optimizing macrolide antibiotics.

Abstract Image

鲍曼不动杆菌大环内酯磷酸转移酶 E 的晶体结构
鲍曼不动杆菌(A. baumannii)对多种抗生素具有耐药性,给临床感染治疗带来了挑战。核心基因组中的多个耐药基因或移动元件导致了鲍曼不动杆菌的多药耐药性。在鲍曼不动杆菌中发现了大环内酯磷酸转移酶基因 mphE,它与大环内酯类抗生素特别相关。在这里,我们测定了 MphE 蛋白在三种状态下的结构:apo 状态、与红霉素和三磷酸鸟苷(GTP)的复合状态以及与阿奇霉素和鸟苷的复合状态。有趣的是,在与红霉素结合的 MphE 复合物中观察到了 GTP 和两个镁离子。这种结构捕捉到了 MphE 的活性状态,其中镁离子稳定了活性位点,并协助了磷酸基团的转移。基于这些结构,我们验证了保守残基 Asp29、Asp194、His199 和 Asp213 在 MphE 催化磷酸化导致耐药性的过程中发挥了重要作用。我们的工作有助于了解耐药性的分子基础,并为优化大环内酯类抗生素提供了参考目标。
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来源期刊
ACS Infectious Diseases
ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES
CiteScore
9.70
自引率
3.80%
发文量
213
期刊介绍: ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.
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