3 years ago

Novel Inhibitors of Staphyloxanthin Virulence Factor in Comparison with Linezolid and Vancomycin versus Methicillin-Resistant, Linezolid-Resistant, and Vancomycin-Intermediate Staphylococcus aureus Infections in Vivo

Novel Inhibitors of Staphyloxanthin Virulence Factor in Comparison with Linezolid and Vancomycin versus Methicillin-Resistant, Linezolid-Resistant, and Vancomycin-Intermediate Staphylococcus aureus Infections in Vivo
Jin Zhu, Feifei Chen, Wenhua Chen, Yanli Lu, Xiaoxia Qiu, Jian Li, Dazheng Lin, Linhao Hu, Yixiang Xu, Fei Mao, Shuaishuai Ni, Yifu Liu, Xinyu Zheng, Hanwen Wei, Manjiong Wang, Wenwen Liu, Baoli Li, Lefu Lan, Xiaokang Li
Our previous work (Wang et al. J. Med. Chem. 2016, 59, 4831−4848) revealed that effective benzocycloalkane-derived staphyloxanthin inhibitors against methicillin-resistant Staphylococcus aureus (S. aureus) infections were accompanied by poor water solubility and high hERG inhibition and dosages (preadministration). In this study, 92 chroman and coumaran derivatives as novel inhibitors have been addressed for overcoming deficiencies above. Derivatives 69 and 105 displayed excellent pigment inhibitory activities and low hERG inhibition, along with improvement of solubility by salt type selection. The broad and significantly potent antibacterial spectra of 69 and 105 were displayed first with normal administration in the livers and hearts in mice against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate S. aureus), and NRS271 (linezolid-resistant S. aureus), compared with linezolid and vancomycin. In summary, both 69 and 105 have the potential to be developed as good antibacterial candidates targeting virulence factors.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00949

DOI: 10.1021/acs.jmedchem.7b00949

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