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18. Design and Synthesis of S-ribosylhomocysteine Analogues

Author

Chbib, Christiane and Chbib, Christiane

Abstract

Bacteria are known to release a large variety of small molecules known as autoinducers (AI) which effect quorum sensing (QS) initiation. The interruption of QS effects bacterial communication, growth and virulence. Three novel classes of S-ribosylhomocysteine (SRH) analogues as potential inhibitors of S-ribosylhomocysteinase (LuxS enzyme) and AI-2 modulators of QS were developed. The synthesis of 2-deoxy-2-bromo-SRH analogues was attempted by coupling of the corresponding 2-bromo-2-deoxypentafuranosyl precursors with the homocysteinate anion. The displacement of the bromide from C2 rather than the expected substitution of the mesylate from C5 was observed. The synthesis of 4-C-alkyl/aryl-S-ribosylhomocysteine analogues involved the following steps: (i) conversion of the D-ribose to the ribitol-4-ulose; (ii) diastereoselective addition of various alkyl or aryl or vinyl Grignard reagents to 4-ketone intermediate; (iii) oxidation of the primary hydroxyl group at C1 followed by the intramolecular ring closure to the corresponding 4-C-alkyl/aryl-substituted ribono-1,4-lactones; (iv) displacement of the activated 5-hydroxyl group with the protected homocysteinate. Treatment of the 4-C-alkyl/aryl-substituted SRH analogues with lithium triethylborohydride effected reduction of the ribonolactone to the ribose (hemiacetal) and subsequent global deprotection with trifluoroacetic acid provided 4-C-alkyl/aryl-SRHs. The 4-[thia]-SRH were prepared from the 1-deoxy-4-thioribose through the coupling of the α-fluoro thioethers (thioribosyl fluorides) with homocysteinate anion. The 4-[thia]-SRH analogues showed concentration dependent effect on the growth on las (50% inhibitory effect at 200 µg/mL). The most active was 1-deoxy-4-[thia]-SRH analogue with sufur atom in the ring oxidized to sulfoxide decreasing las gene activity to approximately 35% without affecting rhl gene. Neither of the tested compounds had effect on bioluminescence nor on total growth of V. harveyi, but had however

Published
2014

21. Pre-clinical Impact of the Synergistic Mechanism of Daptomycin and Ceftaroline on Patients with Methicillin-resistant Staphylococcus aureus Bacteremia Infections.

Author

Eliazar J, Johnson T, and Chbib C

Subjects
Anti-Bacterial Agents pharmacology, Cephalosporins pharmacology, Humans, Ceftaroline, Bacteremia drug therapy, Daptomycin pharmacology, Methicillin-Resistant Staphylococcus aureus
Abstract

Background: Our study aims at assessing the pre-clinical impact of the synergistic mechanism of Daptomycin (DAP) and Ceftaroline (CFT) on patients with Methicillin-Resistant Staphylococcus aureus Bacteremia infections (MRSAB)., Methods: A systematic overview was conducted by searching PubMed, Oxford academic, and Cochrane library up to June 2020., Study Selection and Data Extraction: All English- language clinical trials, in vitro studies, and case reports related to the synergistic drug therapy for MRSAB., Results: In the case of MRSAB infections, we examined two different in vitro studies that showed effective synergism with DAP and CFT. The Minimum Inhibitory Concentration (MIC) range observed for each is as follow: DAP 0.125-1 mg/L, CFT 0.38-1 mg/L, DAP + CFT 0.094-0.5 mg/L, vancomycin (VAN) 0.75-2 mg/L, VAN + CFT 0.25-2 mg/L. DAP + CFT combination displayed the most efficacy with the lowest MIC. The statistical analysis performed showed that DAP + CFT obtained significantly lower fractional inhibitory concentration (FIC) values (0.941 ± 0.328) compared with VAN + CFT. In vitro activities of regimens tested on DAP non-susceptibility and VAN intermediate after 96 hours showed DAP 8.29 ± 0.03 a log 10 CFU/mL, VAN 6.82 ± 0.04 a log 10 Colony Forming Unit (CFU)/mL, CFT 4.63 ± 0.19 a log 10 CFU/mL, DAP + CFT 1.15 ± 0.20 b log 10 CFU/mL, VAN + CFT 3.18 ± 0.49 a log 10 CFU/mL. ( a meaning significantly different than DAP plus CFT, P< equal to 0.001 b meaning therapeutic enhancement combination was defined as ≥ 2 log 10 CFU/ml reduction over the most active single agent). Based on these results, although DAP was not susceptible, the Colony Forming Unit (CFU) for DAP and CFT had the best therapeutic results., Conclusion: In vitro studies have shown that a combination DAP and CFT is more efficacious than the combination of VAN and CFT in MRSA bacteremia infections. The synergic effects of DAP (bactericidal) and CFT (bactericidal) is statistically significant, in recent trials, warranting promising evidence for its use in complicated bacteremia infection., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Published
2021
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