Open AccessModular Design of Membrane-Active Antibiotics: From Macromolecular Antimicrobials to Small Scorpionlike Peptidomimetics
Author(s) -
Minghui Wang,
Xiaoqian Feng,
Ruixuan Gao,
Peng Sang,
Xin Pan,
Lulu Wei,
Chao Lü,
Chuanbin Wu,
Jianfeng Cai
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00312
Subject(s) - antimicrobial , chemistry , peptidomimetic , antibiotics , ciprofloxacin , staphylococcus aureus , microbiology and biotechnology , multiple drug resistance , antibiotic resistance , pharmacology , bacteria , biochemistry , biology , peptide , organic chemistry , genetics
Infections caused by multidrug-resistant bacteria have emerged in recent decades, leading to escalating interest in host defense peptides (HDPs) to reverse this dangerous trend. Inspired by the modular design in bioengineering, herein we report a new class of small amphiphilic scorpionlike peptidomimetics based on this strategy. These HDP mimics show potent antimicrobial activity against both Gram-positive and Gram-negative bacteria without drug resistance but with a high therapeutic index. The membrane-compromising action mode was suggested to be their potential bactericidal mechanism. Pharmacodynamic experiments were conducted using a murine abscess model of methicillin-resistant Staphylococcus aureus (MRSA) infections. The lead compound 12 showed impressive in vivo therapeutic efficacy with ∼99.998% (4.7log) reduction in skin MRSA burden, a significantly higher bactericidal efficiency than ciprofloxacin, and good biocompatibility. These results highlight the potential of these HDP mimics as novel antibiotic therapeutics.