| In Vitro and In Silico Studies of Enterobactin-Inspired Ciprofloxacin and Fosfomycin First Generation Conjugates on the Antibiotic Resistant E. coli OQ866153 |
| Paper ID : 1115-ISCHU |
| Authors |
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Mohamed Tawfik Khazaal1, Ahmed Hassan Faraag2, Hoda Hamed El-Hendawy *3 1Botany & Microbiology Department, Faculty of Science, Helwan University, Cairo, Egypt. 2Botany and Microbiology Department, Faculty of Science, Helwan University, Cairo, Egypt 3Botany and Microbiology Department Faculty of Science Helwan University Helwan Cairo Egypt |
| Abstract |
| The ability of bacteria to develop antimicrobial resistance poses a worldwide problem in the treatment of bacterial infections. To overcome drug resistance caused by permeability issues, the "Trojan Horse" strategy can be employed. This strategy utilizes bacterial iron uptake systems to enter and eliminate bacteria, wherein the siderophore-drug complex is recognized by specific siderophore receptors and actively transported across the outer membrane. In this study, enterobactin, a mixed ligand of the antibiotic resistant Escherichia coli OQ866153, was combined with Ciprofloxacin and Fosfomycin individually to aid active absorption via particular enterobactin binding proteins (FepABCDG), bypass the typical permeability issue caused by efflux proteins (AcrB and TolC), and amplify their effectiveness. Interestingly, Fe+3-enterobactin enhanced the bactericidal activity of Ciprofloxacin (MIC=31.25 µg/ml) and Fosfomycin (MIC=500 µg/ml) against E. coli OQ866153, with a reduction of 3.66 and 5.7 log10 cfu/ml 24 h post-treatment, respectively. The Fe+3-enterobactin-Ciprofloxacin conjugate effectively inhibited the DNA gyrase enzyme (Docking score = -8.597 kcal/mol) and resulted in a lower concentration (25 μg/ml) required to eliminate supercoiled DNA plasmids compared to the parent drug (35 μg/ml; Docking score = -6.264 kcal/mol). The Fe+3-Enterobactin-Fosfomycin conjugate showed a higher inhibition percentage (100%) of biofilm formation compared to Fosfomycin (21.58%) at a concentration of 2 mg/ml, with docking scores of -5.481 and -3.756 kcal/mol against UDP-N acetylglucosamine 1-carboxyvinyltransferase MurA. These findings confirm that the effective implementation of the Trojan Horse antibiotic strategy depends on the successful delivery of the conjugate into the bacterial cell via active siderophore transporters. |
| Keywords |
| Antimicrobial therapy, Enterobactin, Siderophores, Siderophore-drug conjugate "Trojan Horse" strategy. |
| Status: Abstract Accepted (Poster Presentation) |