Speaker:
Austin Dome
Anti-infectives are critical tools for the treatment of infectious diseases, but the use of anti-infectives drives resistance. Despite this, few new anti-infectives are entering into therapeutic use, meaning that anti-infective resistance is outpacing development. The development of new anti-infectives is necessary to address this. Antibiotics and antifungals are of special interest, owing to the broad emergence of antibiotic resistance and the limited tools available for antifungal treatments. To combat resistance, we developed a new class of antifungals targeting calcineurin, a phosphatase enzyme responsible for fungal stress response and survival in human infections. Though the inhibition of calcineurin is potently fungicidal, calcineurin has been precluded as an antifungal target due to conservation of calcineurin in humans, where calcineurin is responsible for immune activation. There are, however, structural differences between human and fungal calcineurin that may be exploited to design calcineurin inhibitors that maintain antifungal activity while abolishing immunosuppression. Modification of FK520, a natural product that inhibits both human and fungal calcineurin, may enable selective antifungal activity. This work details the synthesis of a series of derivatives of FK520 with antifungal activity and reduced immunosuppressive activity and identified C22 and C32 modified compounds that maintain antifungal activity against Candida albicans and Cryptococcus neoformans in vitro while reducing in vivo immunosuppression. In doing so, this work advances the development of calcineurin as a target for antifungal development.
Gram-negative bacterial infections are especially difficult to treat owing to their outer membrane, which limits the permeation of antibiotics into the cell. The anchor of the lipopolysaccharide layer of the outer membrane is produced by the Raetz pathway; the phosphatase enzyme LpxH of the Raetz pathway is of particular interest for antibiotic development as its inhibition both disrupts the bacterial outer membrane and leads to the accumulation of toxic glucosamines, a dual mechanism of bactericidal activity. This work details the development, optimization, characterization, and biological evaluation of a series of LpxH inhibitors, focusing on four areas of improvement and has led to the development of LpxH inhibitors with in vitro activity against Klebsiella pneumoniae and Escherichia coli and sub-nanomolar inhibition of LpxH.