title: Design, synthesis, and structure-activity relationships of benzophenone-based tetraamides as novel antibacterial agents.
abstract: The increase in the incidence of both hospital- and community-acquired antibiotic-resistant infections is a major concern to the healthcare community. There have been only two new classes of antibiotics approved by the FDA over the past 40 years, and clearly there is a growing need for additional antimicrobial agents. In this paper, we present our work on the discovery of a class of benzophenone containing compounds that possess good activity against MRSA, VISA, VRSA, and VRE and moderate activity against E. coli. These compounds display MIC values in the 0.5-2.0 mg/L range and are not cytotoxic against mammalian cells. Extensive structure-activity relationship studies revealed that the benzophenone was absolutely essential for antibacterial activity as was the presence of a cationic group. Although these agents display DNA binding activity, we observed that these compounds do not inhibit any macromolecular synthesis reliant upon DNA nor do they inhibit lipid or cell wall biosynthesis. Instead, we found that these agents cause membrane depolarization, indicating that the bacterial membrane was the primary site of action for these agents. Our studies suggest that caution should be taken in assigning the mechanism of action for DNA binding antibiotics.
authors: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy, Wayne State University, Detroit, MI 48201, USA.
authors: Sunil K
authors: SK
authors: Vooturi
authors: Chrissy M
authors: CM
authors: Cheung
authors: Michael J
authors: MJ
authors: Rybak
authors: Steven M
authors: SM
authors: Firestine
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001577:Benzophenones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004269:DNA, Bacterial / Q000096:biosynthesis; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D014176:Protein Biosynthesis / Q000187:drug effects; D012329:RNA, Bacterial / Q000096:biosynthesis; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000900:Anti-Bacterial Agents; D001577:Benzophenones; D004269:DNA, Bacterial; D012329:RNA, Bacterial