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DOE OSTI · 2482451

Self-Assembling and Pore-Forming Peptoids as Antimicrobial Biomaterials

Jian, Tengyue·Wang, Minghui·Hettige, Jeevapani·Li, Yuhao·Wang, Lei·Gao, Ruixuan·Yang, Wenchao·Zheng, Renyu·Zhong, Shengliang·Baer, Marcel D.·Noy, Aleksandr·De Yoreo, James. J.·Cai, Jianfeng·Chen, Chun-Long
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Abstract

Bacterial infections have been a serious threat to mankind throughout history. Natural antimicrobial peptides (AMPs) and their membrane-disruption mechanism have generated an immense interest in the design and development of synthetic mimetics that could overcome the intrinsic drawbacks of AMPs, such as their susceptibility to proteolytic degradation. Herein, by exploiting the self-assembly and pore-forming capabilities of sequence-defined peptoids, we discovered a new family of low molecular weight peptoid antibiotics that exhibit excellent broad-spectrum activity and high selectivity toward a panel of clinically significant Gram-positive and Gram-negative bacterial strains, including vancomycin-resistant E. faecalis (VREF), methicillin-resistant S. aureus (MRSA), methicillin-resistant S. epidermidis (MRSE), E. coli, P. aeruginosa, and K. pneumoniae. Tuning peptoid sidechain chemistry and structure enabled us to tune the efficacy of antimicrobial activity. Mechanistic studies using Transmission Electron Microscopy (TEM), bacterial membrane depolarization and lysis, and time-kill kinetics assays along with molecular dynamics simulations reveal that these peptoids kill both Gram-positive and Gram-negative bacteria through a membrane-disruption mechanism. In conclusion, these robust and biocompatible peptoid-based antibiotics can provide a valuable tool for combating the emerging drug resistance.

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59 BASIC BIOLOGICAL SCIENCESAntimicrobial activitypeptoidpore-formationself-assembly

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Jian, Tengyue, Wang, Minghui, Hettige, Jeevapani, Li, Yuhao, Wang, Lei, Gao, Ruixuan, Yang, Wenchao, Zheng, Renyu, Zhong, Shengliang, Baer, Marcel D., Noy, Aleksandr, De Yoreo, James. J., Cai, Jianfeng, Chen, Chun-Long. 2024-08-15. Self-Assembling and Pore-Forming Peptoids as Antimicrobial Biomaterials. https://doi.org/10.1021/acsnano.4c05250

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