New and Potent Quinuclidine-Based Antimicrobial Agents

• Published in: Molecules (Basel, Switzerland) Vol. 24; no. 14; p. 2675
• Main Authors: Radman Kastelic, Andreja, Odžak, Renata, Pezdirc, Iskra, Sović, Karlo, Hrenar, Tomica, Čipak Gašparović, Ana, Skočibušić, Mirjana, Primožič, Ines
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23.07.2019; MDPI
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antibiotic resistance; Antibiotics; Antiinfectives and antibacterials; Antimicrobial activity; Antimicrobial agents; antimicrobial potency; Bacillus cereus - drug effects; Bacillus cereus - growth & development; Bacteria; Biological activity; Cell growth; Cell lines; Clostridium perfringens - drug effects; Clostridium perfringens - growth & development; Drug Design; Drug resistance; Enterococcus faecalis - drug effects; Enterococcus faecalis - growth & development; Escherichia coli - drug effects; Escherichia coli - growth & development; FDA approval; Functional groups; Gentamicin; Gentamicins - pharmacology; Global health; Gram-negative bacteria; gram-positive and gram-negative bacteria; Gram-positive bacteria; Klebsiella; Klebsiella pneumoniae - drug effects; Klebsiella pneumoniae - growth & development; Microbial Sensitivity Tests; Microorganisms; Minimum inhibitory concentration; multi-way analysis; Multidrug resistance; Multifactor Dimensionality Reduction; Natural products; Nitrogen; Nosocomial infections; Oximes; Oximes - chemical synthesis; Oximes - pharmacology; Pathogens; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - growth & development; Public health; Quinuclidines - chemical synthesis; Quinuclidines - pharmacology; quinuclidinium oximes; Staphylococcus aureus - drug effects; Staphylococcus aureus - growth & development; United States > US; antimicrobial potency; quinuclidinium oximes; multi-way analysis; gram-positive and gram-negative bacteria
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24142675

Developing new antibiotics is currently very important since antibiotic resistance is one of the biggest problems of global health today. In the search for a new class of potential antimicrobial agents, ten new compounds were designed and synthesized based on the quinuclidinium heterocyclic core and the oxime functional group. The antimicrobial activity was assessed against a panel of representative gram-positive and gram-negative bacteria. All compounds demonstrated potent activity against the tested microorganisms, with the minimum inhibitory concentration (MIC) values ranging from 0.25 to 256.00 μg/mL. Among the tested compounds, two quaternary compounds, - -chlorobenzyl and - -bromobenzyl quinuclidinium oximes, displayed the most potent and broad-spectrum activity against both gram-positive and gram-negative bacterial strains (MIC values from 0.25 to 4.00 μg/mL), with the lowest value for the important multidrug resistant gram-negative pathogen . In the case of , activity of those compounds are 256-fold and 16-fold better than gentamicin, respectively. MTT assays showed that compounds are nontoxic for human cell lines. Multi-way analysis was used to separately reduce dimensionality of quantum chemical data and biological activity data to obtain a regression model and the required parameters for the enhancement of biological activity.