201. Development of guanidine derivatives and CO-releasing agents : a novel approach in the treatment of drug resistant bacterial infections
- Author
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Kim, Seong Heun, Bruce, Kenneth, and Castagnolo, Daniele
- Abstract
Bacterial infections, which have been susceptible to standard antibiotic regimes for decades, are now becoming resistant to all major antimicrobial treatments, undermining the efficacy of available antibiotics. Bacteria can naturally develop resistance over time as they are exposed to antibiotics. However, due to poor economic incentives and challenging regulatory requirements, antibiotic resistance is accelerated mainly by the overuse and misuse of these medications and a lack of new drug development by the pharmaceutical industry. This highlights the need for novel therapeutic approaches to tackle resistant bacterial infections. Herein, different therapeutic strategies targeting antibiotic-resistant bacteria were investigated. The therapeutic approach based on the use of membrane-disrupting agents to enhance the effectiveness of existing antibiotics for the treatment of antibiotic-resistant bacterial infections is suggested. Antibiotics such as rifampicin are known to have poor activity against Gram-negative bacteria owing to the outer membrane, which prevents their efficient uptake. To overcome this challenge, two series of compounds were designed and synthesised, referred to as Lipoguanidines and photoswitchable guanidines. Lipoguanidine compounds consist of a guanidine moiety, which gives selectivity toward bacterial membrane with its positive charge, and a 'lipo' component which can be intercalated and interact with the hydrophobic cytoplasmic membrane of bacteria. Lipoguanidine compounds showed a broad spectrum of excellent membrane permeabilising activity as they reduced the Minimum Inhibitory Concentration of antibiotics with no toxicity observed in Galleria mellonella assays. The structure of photoswitchable guanidines is based on lipoguanidine but also contains photoswitchable moiety that can change conformation upon light irradiation, enhancing their membrane-disrupting activity. Its ability to modulate the abacterial membrane via light irradiation was also observed. The use of light-activated CO-releasing molecules (PhotoCORMs) against multi-drug-resistant bacteria was proposed. CORMs have recently attracted interest in microbiology as it has been shown that CO can exert rapid bactericidal activity when it is delivered through CORMs. Two series of photoactivable PhotoCORMs were designed and synthesised, phenanthroline and flavonols-based PhotoCORMs. Phenanthroline-based PhotoCORMs were effective at low concentrations against multidrug-resistant K. pneumoniae and A. baumannii when photoactivated with blue light. It has also been shown to inhibit the formation of biofilms. The antibacterial and biofilm inhibitory effects are plausibly due to the release of CO and the formation of phenanthroline photo by-products. Besides phenanthroline-based PhotoCORMs, organic molecule-based CORMs include flavonols and flavonoid metal complexes were also synthesised, and its biological activity were evaluated against bacteria. These novel therapeutic approaches demonstrate promising antibacterial activity to combat multidrug-resistant bacterial infection. These new approaches share the insight of sustainable use of antibiotics as they can extend the lifespan of current antibiotics by improving their efficient uptake via membrane-disrupting activity as well as the application of photopharmacology can avoid the emergence of antibiotic resistance via selective activation upon light irradiation.
- Published
- 2023