Development of Oxadiazole-Sulfonamide-Based Compounds as Potential Antibacterial Agents

Abstract

In this work, substituted 1,2,4-oxadiazoles (<b>OX1</b>-<b>OX27</b>) were screened against five bacterial strains, identified to be <b>OX7</b> and <b>OX11</b> as growth inhibitors with minimum inhibitory concentration (MIC) values of 31.25 and 15.75 μg/mL, respectively. The growth inhibitory property of <b>OX7</b> and <b>OX11</b> was further validated by disk diffusion, growth curve, and time kill curve assays. Both disrupted biofilm formation with 92-100% reduction examined by the XTT assay were further visualized by scanning electron microscopy analysis. These compounds in combination with ciprofloxacin also exhibit synergy against <i>Escherichia coli</i> cells. With insignificant cytotoxic behavior on HEK293 cells, human red blood cells, and <i>Galleria mellonella</i> larvae, <b>OX11</b> was tested against 28 multidrug resistant environmental isolates of bacteria and showed inhibition of <i>Kluyvera georgiana</i> and <i>Citrobacter werkmanii</i> strains with 32 and 16 μg/mL MIC values, respectively. The synergistic behavior of <b>OX11</b> with ampicillin showed many fold reductions in MIC values against <i>K. georgiana</i> and <i>Klebsiella pneumoniae</i> multidrug resistant strains. Further, transmission electron microscopy analysis of <b>OX11</b>-treated <i>E. coli</i> cells showed a significantly damaged cell wall, which resulted in the loss of integrity and cytosolic oozing. <b>OX11</b> showed significant changes in the secondary structure of human serum albumin (HSA) in the presence of <b>OX11</b>, enhancing HSA stability. Overall, the study provided a suitable core for further synthetic alterations and development as an antibacterial agent.