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<p>Several thionated levofloxacin (LVX) derivatives were designed and synthesized to enhance antimicrobial effects. In this study, compounds <b>2</b> and <b>3</b> (thionated LVX derivatives) were evaluated against bacteria and fungi. Molecular docking was performed for the lead compound and LVX on bacterial topoisomerases. LC–MS analysis was performed to obtain metabolic profiling. Compound <b>3</b> exhibited the strongest antibacterial activity against the tested bacterial strains, with a maximum zone of inhibition of 31&#xa0;mm at 2&#xa0;mM against <i>Shigella flexneri</i>. Compound <b>3</b> was also highly active against <i>Shigella flexneri</i> with an MIC value of 0.0156&#xa0;µM and an MBC value of 0.0312&#xa0;µM. Compound <b>2</b> lacked antibacterial activity. In addition, compounds <b>2</b> and <b>3</b> lacked antifungal activity. Molecular docking showed that compound <b>3</b> binds favorably to DNA gyrase and DNA topoisomerase IV with the lowest binding energy scores of − 8.54 and − 10.11&#xa0;kcal/mol, respectively, which were close to LVX scores. LC–MS analysis for the sample prepared following the incubation of <i>K. pneumoniae</i> with compound <b>3</b> showed a major peak with retention time at 6.03&#xa0;min and a protonated molecular ion at <i>m/z</i> 362.15, both of which correspond to LVX standard. LC–MS analysis for compound <b>3</b> showed a peak with retention time of 6.40&#xa0;min and a protonated molecular ion at <i>m/z</i> 377.12. These findings may suggest the biodesulfurization and subsequent activation of compound <b>3</b> to LVX, which indicates that compound <b>3</b> may act as a prodrug. The presence of sulfur in compound <b>3</b> may have enhanced penetration to bacteria and may also do the same for biofilms.</p>

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Biodesulfurization and activation of a thionated levofloxacin derivative: antimicrobial evaluation and LC–MS-based metabolic profiling

  • 期刊论文

  • 发表日期：

    2026年5月1日

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  • Osama H. Abusara,
  • Hamza Abumansour,
  • Mohammad Abu-Sini,
  • Morad Mustafa,
  • Rawan Huwaitat,
  • Abdel Qader Al Bawab,
  • Ahmad A. Deeb,
  • Hassan Abul-Futouh,
  • Dina H. Abulebdah,
  • Wasan Al-Hadban,
  • Ali I. M. Ibrahim

摘要

Several thionated levofloxacin (LVX) derivatives were designed and synthesized to enhance antimicrobial effects. In this study, compounds 2 and 3 (thionated LVX derivatives) were evaluated against bacteria and fungi. Molecular docking was performed for the lead compound and LVX on bacterial topoisomerases. LC–MS analysis was performed to obtain metabolic profiling. Compound 3 exhibited the strongest antibacterial activity against the tested bacterial strains, with a maximum zone of inhibition of 31 mm at 2 mM against Shigella flexneri. Compound 3 was also highly active against Shigella flexneri with an MIC value of 0.0156 µM and an MBC value of 0.0312 µM. Compound 2 lacked antibacterial activity. In addition, compounds 2 and 3 lacked antifungal activity. Molecular docking showed that compound 3 binds favorably to DNA gyrase and DNA topoisomerase IV with the lowest binding energy scores of − 8.54 and − 10.11 kcal/mol, respectively, which were close to LVX scores. LC–MS analysis for the sample prepared following the incubation of K. pneumoniae with compound 3 showed a major peak with retention time at 6.03 min and a protonated molecular ion at m/z 362.15, both of which correspond to LVX standard. LC–MS analysis for compound 3 showed a peak with retention time of 6.40 min and a protonated molecular ion at m/z 377.12. These findings may suggest the biodesulfurization and subsequent activation of compound 3 to LVX, which indicates that compound 3 may act as a prodrug. The presence of sulfur in compound 3 may have enhanced penetration to bacteria and may also do the same for biofilms.