Infectious diseases are the 2nd leading cause of death worldwide and pose a global health problem that requires constant effort towards the discovery of new anti-infective drugs. One driver for anti-infective drug development is the inevitable emergence of drug resistant pathogens, which are no longer susceptible to traditional therapeutic strategies. Another driver is that the absence of therapeutic agents that are effective against troublesome infective agents. Given these challenges, development programs for new anti-infective small-molecule therapeutics are often directed towards the identification and validation of new drug targets. This thesis discusses the development of drug leads with targets that are not yet exploited by clinically used small molecule therapeutics. We have discovered dihydroquinazolinones (DHQs) that modulate host retrograde trafficking. By targeting a host cellular factor, these small molecules exhibit a broad therapeutic scope. Infection by human polyomavirus and papillomavirus, as well as intoxication by deadly toxins such as ricin and Shiga-like toxins are inhibited by these remarkable compounds. Additionally, we have discovered remarkably potent acyldepsipeptide (ADEP) antibacterial agents that target bacterial proteolysis. Because of their distinct mechanism of action, ADEPs are toxic to bacteria that have become resistant to clinically used antibiotics. Our medicinal chemistry optimization of the ADEPs has led to the discovery of some of the most potent antibacterial agents ever reported and we have shown that they are effective in mouse models of bacterial infection. It is our hope that continued development of these anti-infective drug strategies will lead to clinically useful small molecule therapeutics.
Carney, Daniel W.,
"Chemical Syntheses and Evaluations of Novel Anti-Infective Small Molecules"
(2014).
Chemistry Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.7301/Z09C6VSK
