Improvement of small molecule ClpP activators for use in hybrid antibiotics - Project Summary Antibiotic-resistant pathogens are an ongoing clinical crisis as multi-drug resistance increases the rate of treatment failure. Staphylococcus aureus (S. aureus), a Gram-positive pathogen, is considered a serious threat by the CDC due to the emergence of resistant populations and its propensity to form biofilms, limiting the antibiotics that can be used for treatment. Patient populations with compromised immune systems, such as those here at St. Jude Children’s Research Hospital, are at a high risk of developing biofilm infections through implanted devices that are administering lifesaving care. A class of natural products, the acyldepsipeptides (ADEPs) have activity against biofilm infections due to their ability to activate caseinolytic protease subunit P (ClpP), a non-essential conserved protease in Gram-positive bacteria. ADEP binding displaces the ATP- regulated chaperone protein, leading to uncontrolled proteolysis and cell death. Previous work in our lab has generated a ureadepsipeptide (UDEP), which improves the stability, selectivity, and potency of the original ADEP. However, the high mutation frequency of ClpP limits its use as an antibiotic target. When co-dosing ClpP activators with rifampin, there is a drastic reduction in the emergence of resistance and an additive decrease in bacterial burden in vivo. To better control tissue distribution, our lab conjugated the lead UDEP compound to rifampin to generate a hybrid compound called chimerabactin. Chimerabactin has dual-target engagement and decreased resistance rates in S. aureus, but the molecule requires a complicated synthesis route with a minimum of 21 steps and is over 25 Å in size, so there is an imminent need for structural modifications. I propose an approach in which we improve on a small molecule ClpP activator series and establish the feasibility of using this series instead of the UDEP compound. I will use computational modeling and QSAR studies to inform chemical design before synthesis and validation using previously established workflows in the lab.
