Potentiation of Vancomycin: Creating Cooperative Membrane Lysis through a "Derivatization-for-Sensitization" Approach

Lei, E.1,2; Tao, Huanyu3; Jiao, Shang4; Yang, Anming1,2; Zhou, Yu1,2; Wang, Min1,2; Wen, Kang1,2; Wang, Yi1,2,5,6; Chen, Zhiyong1,2; Chen, Xianhui1,2; Song, Junfeng1,2; Zhou, Cailing1,2,5,6; Huang, Wei1,2,4; Xu, Lili4; Guan, Dongliang4; Tan, Cuiyan7; Liu, Haoran1,2; Cai, Qingyun1,2; Zhou, Kai8; Modica, Justin9,10; Huang, Sheng-You3; Huang, Wei4; Feng, Xinxin1,2

2022-06-15

10.1021/jacs.2c03784

Journal of the American Chemical Society   Impact Factor & Quartile

0002-7863

1520-5126

Gram-negative bacteria, especially the ones with multidrug resistance, post dire challenges to antibiotic treatments due to the presence of the outer membrane (OM), which blocks the entry of many antibiotics. Current solutions for such permeability issues, namely lipophilic-cationic derivatization of antibiotics and sensitization with membrane-active agents, cannot effectively potentiate the large, globular, and hydrophilic antibiotics such as vancomycin, due to ineffective disruption of the OM. Here, we present our solution for high-degree OM binding of vancomycin via a hybrid "derivatization-for-sensitization" approach, which features a combination of LPS-targeting lipo-cationic modifications on vancomycin and OM disruption activity from a sensitizing adjuvant. 10(6)- to 10(7)-fold potentiation of vancomycin and 20-fold increase of the sensitizer's effectiveness were achieved with a combination of a vancomycin derivative and its sensitizer. Such potentiation is the result of direct membrane lysis through cooperative membrane binding for the sensitizer-antibiotic complex, which strongly promotes the uptake of vancomycin and adds to the extensive antiresistance effectiveness. The potential of such derivatization-for-sensitization approach was also supported by the combination's potent in vivo antimicrobial efficacy in mouse model studies, and the expanded application of such strategy on other antibiotics and sensitizer structures.

SCI

English

NI Journal Papers

Others

National Natural Science Foundation of China[21807031,22177031,62072199,32161133002,21874038,92153301] ; Open Funding Project of the State Key Laboratory of Biocatalysis and Enzyme Engineering[SKLBEE2019003] ; Natural Science Foundation of Hunan Province, China[2020JJ4177]

Chemistry

Chemistry, Multidisciplinary

WOS:000812548300001

AMER CHEMICAL SOC

Web of Science

1.Hunan Univ, Inst Chem Biol & Nanomed, State Key Lab Chemo Biosensing & Chemometr, Hunan Prov Key Lab Biomacromol Chem Biol, Changsha 410082, Hunan, Peoples R China
2.Hunan Univ, Sch Chem & Chem Engn, Changsha 410082, Hunan, Peoples R China
3.Huazhong Univ Sci & Technol, Sch Phys, Wuhan 430074, Hubei, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Ctr Excellence Mol Cell Sci, Ctr Biotherapeut Discovery Res,CAS Key Lab Recept, Shanghai 201203, Peoples R China
5.Hunan Univ, Sch Biol, Changsha 410082, Hunan, Peoples R China
6.Hunan Univ, Changsha 410082, Hunan, Peoples R China
7.Sun Yat Sen Univ, Affiliated Hosp 5, Dept Pulm & Crit Care Med, Zhuhai 519000, Guangdong, Peoples R China
8.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Shenzhen Inst Resp Dis, Shenzhen 518020, Guangdong, Peoples R China
9.Northwestern Univ, Dept Chem, Evanston, IL 60208 USA
10.Northwestern Univ, Dept Biomed Engn, Evanston, IL 60208 USA

Lei, E.,Tao, Huanyu,Jiao, Shang,et al. Potentiation of Vancomycin: Creating Cooperative Membrane Lysis through a "Derivatization-for-Sensitization" Approach[J]. Journal of the American Chemical Society,2022,144(23).

Lei, E..,Tao, Huanyu.,Jiao, Shang.,Yang, Anming.,Zhou, Yu.,...&Feng, Xinxin.(2022).Potentiation of Vancomycin: Creating Cooperative Membrane Lysis through a "Derivatization-for-Sensitization" Approach.Journal of the American Chemical Society,144(23).

Lei, E.,et al."Potentiation of Vancomycin: Creating Cooperative Membrane Lysis through a "Derivatization-for-Sensitization" Approach".Journal of the American Chemical Society 144.23(2022).