| Summary: | 碩士 === 國防醫學院 === 微生物及免疫學研究所 === 91 === Abstract
Recently, more and more drug resistant bacteria emerge as a result of drug abuse by human beings. In order to develop a new antibiotic, compound N-(6-fluoroquinoloyl)-ampicillin, FQ-1 was synthesized by coupling the carboxyl group of 6-fluoroquinolone (FP-4) with the α-amino group of ampicillin in our laboratories. FQ-1 exhibits a broad-spectrum antibacterial activities. In particular, it is active against some clinical isolates of Pseudomonas aeruginosa, which are highly resistant to norfloxacin and/or gentamincin. Protoplast formation study revealed that FQ-1 did not inhibit biosynthesis of the cell wall but did induce cell filamentation of Bacillus subtilis at the level close to its MIC. This implied that FQ-1 might inhibit penicillin binding protein 3 (PBP3) which was required for septum formation. Interestingly, study on the mechanism of antimicrobial action of FQ-1 revealed that FQ-1 could intercalate into double-stranded DNA but not single-stranded DNA. Moreover, two tandem GC sequence was the minimal requirement for FQ-1 intercalation. However, FQ-1 lost its anti- bacterial activity and DNA intercalation activity after it was treated with penicillinase, indicating that the β-lactam ring structure in ampicillin moiety of FQ-1 might be hydrolyzed by penicillinase and the hydrolyzed structure do not own intercalation activity. In the aspect of antiviral activity, our results demonstrated that FQ-1 did inhibit vaccinia virus and replication but didn’t inhibit Japanese Encephalitis Virus (JEV) replication, a single- stranded RNA virus. As compared to rifampin, FQ-1 showed a much lower cytotoxicity to BHK 21 cells than did rifampin. Thus, the therapeutic index of FQ-1 was 7-fold higher than that of rifampin. This suggests that FQ-1 is more potential to be developed as an antiviral drug for clinical use than rifampin.
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