A Novel Class of Cationic and Non-Peptidic Small Molecules as Hits for the Development of Antimicrobial Agents

• Published in: Molecules (Basel, Switzerland) Vol. 23; no. 7; p. 1513
• Main Authors: Jiménez, Aranza, García, Pablo, de la Puente, Sofia, Madrona, Andrés, Camarasa, María José, Pérez-Pérez, María-Jesús, Quintela, José-Carlos, García-Del Portillo, Francisco, San-Félix, Ana
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22-06-2018; MDPI
• Subjects: Aliphatic compounds; Aminophenol; Aminophenols - chemistry; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; antibiotic resistance; Antiinfectives and antibacterials; Antimicrobial activity; Antimicrobial agents; Antimicrobial Cationic Peptides - chemical synthesis; Antimicrobial Cationic Peptides - pharmacology; antimicrobial peptides; Bacteria; Cations; Cell Line; Cell Survival - drug effects; Fibroblasts - cytology; Fibroblasts - drug effects; Gram-negative bacteria; Gram-Negative Bacteria - drug effects; Gram-Negative Bacteria - growth & development; Gram-positive bacteria; Gram-Positive Bacteria - drug effects; Gram-Positive Bacteria - growth & development; HeLa Cells; Humans; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Microbial Sensitivity Tests; Multidrug resistance; Multidrug resistant organisms; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - pharmacology; Species Specificity; Static Electricity; Strains (organisms); Structure-Activity Relationship; antimicrobial agents; antibiotic resistance; antimicrobial peptides
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules23071513

Cationic and non-peptide small molecules containing a total of six positive charges arranged on one side and a long aliphatic tail on the other have been synthesized and tested against Gram-positive and Gram-negative bacteria. The positive charges have been contributed by two aminophenol residues. These molecules have showed remarkable antimicrobial activity against Gram-positive bacteria including multidrug-resistant strains. Our structure⁻activity relationship studies demonstrated the importance of the length and flexibility of the hydrophobic tail for the antimicrobial activity. Importantly, these compounds are non-toxic to eukaryotic cells at the concentration affecting growth in bacteria, reflecting an acceptable margin of safety. The small size and easy synthetic accessibility of our molecules can be of interest for the further development of novel antimicrobials against Gram-positive bacterial pathogens, including multidrug-resistant strains.