We are focused on general aspects of mycobacterial processes that have proven vulnerable to chemical inhibition: transcription, translation, variant central carbon metabolic pathways that are critical for bacterial survival in animal models, protein complexes necessary for cell wall synthesis, and prokaryote-specific essential enzymes that can be selectively inhibited. With strong expertise in biochemistry and structural biology and long standing collaborations with leading groups in mycobacterial genetics we leverage structural insight and novel genetic and chemical-genetic tools to understand mycobacterial biology and specifically identify vulnerabilities of the pathogen that can be exploited for drug design.

In the Sacchettini lab we have been focused on the identification of small molecules that overcome drug resistance in cancer, particularly of lymphomas and ovarian cancers. Through studies of combinations of drugs and chemical compound libraries we have identified a number of compounds which enhance common cancer drugs and allow cancer cells to be controlled again, potentially at a lower dose. From our promising studies, we have patented a series of compounds of the ansamycin class of antibiotics that synergize with numerous commonly administered cancer drugs (Sacchettini et al. 2017, US Patents 9,539,237B2 and 9,867,807B2).

We initiated a SARS-CoV2 drug discovery project seeking to produce a lead for new antiviral. We chose target-based strategy and implement high throughput screening (HTS) focusing on four essential viral proteins, the main protease (Mpro), the papain-like protease (PLpro), the RNA-dependent RNA polymerase (RdRP) and the nidoviral RNA uridylate‐specific endoribonuclease (NendoU). While for some of these targets screening is still ongoing, we already found promising hits using our commercially sourced, in-house ~120k highly diverse small molecule library. A few hits have been followed up under a structure-guided medicinal chemistry optimization and proceeded to lead generation stage.

Infectious diseases, such as malaria, diarrheal disease, and neglected tropical infections kill over 8 million people each year, (Global Burden of Disease 2015, Liu.L et al 2015). Our research interests are focused on biological evaluation of chemical compounds on key human parasites for drug discovery and clinically corroborating these compounds. Our lab currently focuses on parasitic diseases, such as malaria, cryptosporidiosis, and two major kinetoplastid diseases – human African trypanosomiasis (sleeping sickness), and Chagas disease.

Mutations in the P-type copper transporting ATPase, ATP7A, results in severe hereditary copper deficiency known as Menkes disease. Menkes follows an X-linked recessive inheritance pattern with male newborns exhibiting symptomatic illness. Menkes patients present with various hair and connective tissue abnormalities, failure to thrive, severe neurodegeneration, and death typically before three years of age. In the brain, copper deficiency impairs the function of cytochrome c oxidase, a component of mitochondrial electron transport required for energy generation. The Sacchettini Lab is currently developing a treatment strategy based upon restoration of cytochrome c oxidase functions.

At SACLab we continue our efforts towards building open source softwares that support the scientific community.