Browsing by Author "Wang, Xu"

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    A Novel Phosphodiesterase of the GdpP Family Modulates Cyclic di-AMP Levels in Response to Cell Membrane Stress in Daptomycin-Resistant Enterococci
    (2017-04-17) Wang, Xu; Shamoo, Yousif; Olson, John
    Antimicrobial resistance is a serious and growing threat to public health. The Centers for Disease Control estimates that at least 2 million people contract serious infections each year resulting in at least 23,000 deaths each year in the United States alone. To develop more effective treatments, it is important to understand the fundamental biology underlying the mechanisms of antibiotic resistance. Substitutions in the LiaFSR membrane stress response pathway are frequently associated with emergence of antimicrobial peptide resistance in both Enterococcus faecalis and Enterococcus faecium. Cyclic di-AMP (c-di-AMP) is an important signal molecule that affects many aspects of bacterial physiology including stress response. We have previously identified a mutation in a gene (designated yybT) of E. faecalis that was associated with development of daptomycin resistance. The adaptive mutation produced a change at position 440 in the predicted protein (yybTI440S). Here, we show that intracellular cyclic di-AMP signaling is present in enterococci and, based upon in vitro physicochemical characterization, we show that E. faecalis yybT encodes a cyclic dinucleotide phosphodiesterase of the GdpP family that exhibits specific activity toward c-di-AMP by hydrolyzing it to 5’pApA. The E. faecalis GdpPI440S substitution reduces cyclic di-AMP phosphodiesterase activity more than 11-fold leading to further increases in cyclic di-AMP levels. Additionally, deletions of liaR (encoding the response regulator of the LiaFSR system) that lead to daptomycin hypersusceptibility in both E. faecalis and E. faecium also resulted in increased cyclic-di-AMP levels suggesting that changes in the LiaFSR stress response pathway are linked to broader physiological changes. Taken together, our data show that modulation of cyclic di-AMP pools is strongly associated with antibiotic-induced cell membrane stress response via changes in GdpP activity and signaling through the LiaFSR system.
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    Three-dimensional covalent organic frameworks with pto and mhq-z topologies based on Tri- and tetratopic linkers
    (Springer Nature, 2023) Zhu, Dongyang; Zhu, Yifan; Chen, Yu; Yan, Qianqian; Wu, Han; Liu, Chun-Yen; Wang, Xu; Alemany, Lawrence B.; Gao, Guanhui; Senftle, Thomas P.; Peng, Yongwu; Wu, Xiaowei; Verduzco, Rafael
    Three-dimensional (3D) covalent organic frameworks (COFs) possess higher surface areas, more abundant pore channels, and lower density compared to their two-dimensional counterparts which makes the development of 3D COFs interesting from a fundamental and practical point of view. However, the construction of highly crystalline 3D COF remains challenging. At the same time, the choice of topologies in 3D COFs is limited by the crystallization problem, the lack of availability of suitable building blocks with appropriate reactivity and symmetries, and the difficulties in crystalline structure determination. Herein, we report two highly crystalline 3D COFs with pto and mhq-z topologies designed by rationally selecting rectangular-planar and trigonal-planar building blocks with appropriate conformational strains. The pto 3D COFs show a large pore size of 46 Å with an extremely low calculated density. The mhq-z net topology is solely constructed from totally face-enclosed organic polyhedra displaying a precise uniform micropore size of 1.0 nm. The 3D COFs show a high CO2 adsorption capacity at room temperature and can potentially serve as promising carbon capture adsorbents. This work expands the choice of accessible 3D COF topologies, enriching the structural versatility of COFs.