Crucial Role for Lipoteichoic Acid Assembly in the Metabolic Versatility and Antibiotic Resistance of Staphylococcus aureus.

Staphylococcus aureus is a public health threat due to the prevalence of antibiotic resistance and the capacity of this organism to infect numerous organs in vertebrates. To generate energy needed to proliferate within tissues, S. aureus transitions between aerobic respiration and fermentation.

Synthesis and biological activity of conformationally restricted indole-based inhibitors of neurotropic alphavirus replication: Generation of a three-dimensional pharmacophore.

We have previously reported the development of indole-based CNS-active antivirals for the treatment of neurotropic alphavirus infection, but further optimization is impeded by a lack of knowledge of the molecular target and binding site. Herein we describe the design, synthesis and evaluation of a series of conformationally restricted analogues with the dual objectives of improving potency/selectivity and identifying the most bioactive conformation. Although this campaign was only modestly successful at improving potency, the sharply defined SAR of the rigid analogs enabled the definition of a three-dimensional pharmacophore, which we believe will be of value in further analog design and virtual screening for alternative antiviral leads.

Discovery of anthranilamides as a novel class of inhibitors of neurotropic alphavirus replication.

Neurotropic alphaviruses are debilitating pathogens that infect the central nervous system (CNS) and are transmitted to humans via mosquitoes. There exist no effective human vaccines against these viruses, underlining the need for effective antivirals, but no antiviral drugs are available for treating infection once the viruses have invaded the CNS. Previously, we reported the development of novel indole-2-carboxamide-based inhibitors of alphavirus replication that demonstrate significant reduction of viral titer and achieve measurable brain permeation in a pharmacokinetic mouse model.