NOVEL N-(1,3,4-OXADIAZOL-2-YL)BENZAMIDES AS ANTIMICROBIAL AGENTS
thesisposted on 2021-12-04, 00:03 authored by George Alfred NaclerioGeorge Alfred Naclerio
Antibiotic resistance has become a major threat to human health. For instance, globally, it is estimated that more than 700,000 people die annually from infections caused by drug-resistant bacterial pathogens. In the United States, antibiotic resistance is also a major issue as the Centers for Disease Control and Prevention (CDC) reports that more than 2.8 million antibiotic-resistant infections occur each year, resulting in more than 35,000 deaths. At the same time, the antibiotic pipeline remains dry – exemplified by the paucity of novel antibiotics introduced into clinical use and the number of active pharmaceutical companies working on antibiotic development. Still, antibiotics that have either entered clinical trials or have been FDA approved recently are just derivatives of other drugs. This means that resistance mechanisms affecting the older drugs will likely affect the newer ones as well. Therefore, this is a dire need to develop antibiotics containing new chemotypes and novel mechanisms of action to slow down the generation of resistance.
Lipoteichoic acid (LTA) is an anionic polymer attached to the cell membrane of Gram-positive bacteria such as Staphylococcus aureus, Enterococci, Listeria monocytogenes, Streptococcus pneumoniae, and Bacillus subtilis. It’s been found that LTA is highly important for several bacterial processes such as growth, virulence, biofilm formation, and inflammation. Because of this, LTA has been deemed a potential new antibiotic target. Inhibitors of LTA have been reported but they contain several unfavorable properties such as low to moderate antibacterial activity.
This dissertation reports a novel class of sulfonamide containing N-(1,3,4-oxadiazol-2-yl)benzamides which potently inhibit Staphylococcus aureus (S. aureus) LTA biosynthesis with minimum inhibitory concentrations (MICs) of 0.25 µg/mL. Additonally, this dissertation will discuss the discovery of trifluoromethoxy (OCF3), trifluoromethylthio (SCF3) and pentafluorosulfanyl (SF5) containing N-(1,3,4-oxadiazol-2-yl)benzamides exhibiting strong antibacterial activities against a wide-range of clinically important bacterial pathogens such as methicillin-resistant S. aureus (MRSA), vancomycin resistant enterococcus (VRE), Clostridioides difficile (C. difficile), and Neisseria gonorrhoeae (N. gonorrhoeae) with MICs as low as 0.003 µg/mL. Halogenated N-(1,3,4-oxadiazol-2-yl)benzamides which eradicate MRSA preformed biofilm have also been characterized.