Abstract
The emergence and prevalence of multidrug-resistant (MDR) bacteria particularly Gram-negative bacteria presents a global crisis for human health. Colistin and tigecycline were recognized as the last resort of defenses against MDR Gram-negative pathogens. However, the emergence and prevalence of MCR or Tet(X)-mediated acquired drug resistance drastically impaired their clinical efficacy. It has been suggested that antimicrobial peptides might act a crucial role in combating antibiotic resistant bacteria owing to their multiple modes of action and characteristics that are not prone to developing drug resistance. Herein, we report a safe and stable tryptophan-rich amphiphilic peptide termed WRK-12 with broad-spectrum antibacterial activity against various MDR bacteria, including MRSA, colistin and tigecycline-resistant Escherichia coli. Mechanistical studies showed that WRK-12 killed resistant E. coli through permeabilizing the bacterial membrane, dissipating membrane potential and triggering the production of reactive oxygen species (ROS). Meanwhile, WRK-12 significantly inhibited the formation of an E. coli biofilm in a dose-dependent manner. These findings revealed that amphiphilic peptide WRK-12 is a promising drug candidate in the fight against MDR bacteria.
Highlights
Pathogenic bacteria Gram-negative pathogens such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii have been a major cause of systemic infections in clinics [1,2]
We found a stable and potent dodecapeptide termed WRK-12 that could effectively kill various MDR bacteria, including notorious methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococcus (VRE), carbapenem-resistant Enterobacteriaceae (CRE) and mcr-1-positive E. coli (MCRPEC) and tet(X4)-positive bacteria
A collection of tryptophan-rich linear peptides on the basis of MP196 (RWRWRW-NH2) was designed by increasing peptide length or positive charge or hydrophobicity, replacing amino acids and/or N-terminal acetylation (Table 1). These peptides were synthesized via solid-phase peptide synthesis (SPPS), purified by reverse-phase high-performance liquid chromatography (RP-HPLC) (Figure S1) and validated by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) (Figure S2)
Summary
Pathogenic bacteria Gram-negative pathogens such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii have been a major cause of systemic infections in clinics [1,2]. These pathogens have developed multiple acquired resistance against current antimicrobial treatments [3,4,5]. The co-harboring of blaNDM, mcr-1 and/or tet(X) genes in clinical isolates makes it more difficult to treat MDR pathogens’ associated infectious diseases.
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