Synthesis and in Silico Modelling of the Potential Dual Mechanistic Activity of Small Cationic Peptides Potentiating the Antibiotic Novobiocin against Susceptible and Multi-Drug Resistant Escherichia coli

Abstract

Cationic antimicrobial peptides have attracted interest, both as antimicrobial agents and for their ability to increase cell permeability to potentiate other antibiotics. However, toxicity to mammalian cells and complexity have hindered development for clinical use. We present the design and synthesis of very short cationic peptides (3–9 residues) with potential dual bacterial membrane permeation and efflux pump inhibition functionality. Peptides were designed based upon in silico similarity to known active peptides and efflux pump inhibitors. A number of these peptides potentiate the activity of the antibiotic novobiocin against susceptible Escherichia coli and restore antibiotic activity against a multi-drug resistant E. coli strain, despite having minimal or no intrinsic antimicrobial activity. Molecular modelling studies, via docking studies and short molecular dynamics simulations, indicate two potential mechanisms of potentiating activity; increasing antibiotic cell permeation via complexation with novobiocin to enable self-promoted uptake, and binding the E. coli RND efflux pump. These peptides demonstrate potential for restoring the activity of hydrophobic drugs.

Deep Learning for Novel Antimicrobial Peptide Design

“…The positive data set with sequences of length ≤ 15 residues contained 690 sequences. Two sets of negative controls were collected: one containing 1119 sequences from UniProt, selected randomly from the 82,459 sequences found with the search term, and the other containing 142 sequences from the AMP databases and literature [ 64 ]. The sequences had lengths ranging from two to 20, with an average of 14 residues ( Figure S1 ).…”

“…Therefore, all sequences were considered without capping, which leads to designed sequences of uncapped peptides. As the negatively charged C-terminal may adversely affect the interaction of a peptide with the negatively charged membrane of Gram-negative bacteria [ 11 , 64 ], the synthesis of -NH 2 -capped C-terminals should be considered. Additionally, there were some discrepancies in the MIC values reported in the AMP databases for a small set of peptide sequences.…”

The Physical Chemistry and Chemical Physics (PCCP) Section of the International Journal of Molecular Sciences in Its Publications: The First 300 Thematic Articles in the First 3 Years

“…The last one seems to be the most detailed, and it is precisely this that we will try to implement in the course of our narrative. As it should be expected, a priori, most of the publications in this direction are devoted to organic compounds, and primarily organic molecules; these include, with varying degrees of correctness, publications [ 1 , 2 , 3 , 102 , 103 , 104 , 106 , 108 , 112 , 117 , 118 , 119 , 121 , 124 , 127 , 128 , 130 , 131 , 132 , 133 , 135 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 146 , 147 , 148 , 151 , 153 , 154 , 156 , 157 , 164 , 165 , 166 , 168 , 171 , 172 , 174 , 176 , 178 , 180 , 183 , 185 , 186 ]. Much less space is occupied by the works related to polymeric (in fact, to a high molecular weight) compounds [ 113 , …”

Development of Amphiphilic Coumarin Derivatives as Membrane-Active Antimicrobial Agents with Potent In Vivo Efficacy against Gram-Positive Pathogenic Bacteria

“…35,37,38 Gram-positive infections. 35,39,40 At present, these natural coumarin antibiotics still have several obvious shortcomings, including poor water solubility, high toxicity to eukaryotes, and rapid development of bacterial resistance, which greatly restrict their clinical applications. 35 Therefore, effectively solving these shortcomings of coumarin antibiotics has become one of the current research hotspots and difficulties and is very beneficial to solving the current serious problem of bacterial resistance.…”

“…Coumarin derivatives contain a benzo-α-pyrone structure and are widely present in plants and microbial metabolites. , They generally have excellent pharmacokinetic properties and a wide range of pharmacological activities, such as anticoagulant, antiviral, antibacterial activity, etc. ,, Natural coumarin antibiotics such as novobiocin, coumermycin A1, and chlorobiocin have been used clinically for the treatment of Gram-positive infections. ,, At present, these natural coumarin antibiotics still have several obvious shortcomings, including poor water solubility, high toxicity to eukaryotes, and rapid development of bacterial resistance, which greatly restrict their clinical applications . Therefore, effectively solving these shortcomings of coumarin antibiotics has become one of the current research hotspots and difficulties and is very beneficial to solving the current serious problem of bacterial resistance …”