Development of a PO-administered beta-lactam-tarocin combination agent to treat methicillin susceptible and methicillin resistant Staphylococci

The goal of this SBIR Phase IIB proposal is to develop a novel tarocin/-lactam combination agent suitable for oral administration which could be used to safely and effectively treat patients infected by methicillin-susceptible and resistant Staphylococcus aureus & Staphylococcus epidermidis (MSSA, MRSA, MSSE & MRSE). MRSA and MRSE are a major cause of bloodstream infections in the hospital and in the community, and are rising on account of IV drug use fueled by the growing opioid crisis. Indeed, MRSA remains the second leading cause of mortality by drug-resistant bacterial pathogens in the USA. Treatment routinely relies on vancomycin (VAN), daptomycin (DAP), or oxazolidinones such as linezolid (LZD) and tedizolid (TZD), but all of these agents have limitations, including IV-only administration for VAN & DAP, toxicities with prolonged use for LZD & TZD, as well as growing resistance to all. Conversely, β-lactam antibiotics have historically had the greatest impact of any class of antibiotics ever to treat bacterial infections, but their efficacy has been eroded by the emergence of MRSA/E. Reestablishing β-lactams as a standard of care therapy for Gram-positive bacterial infections including MRSA/E would provide clinicians with a new therapeutic option and would allow for improved antibiotic stewardship to mitigate resistance to DAP and LZD. Under a preceding SBIR fast-track grant (R44AI136213), we have discovered and developed a novel class of compounds called tarocins, which selectively inhibit the non- essential enzyme TarO in Staph, and the resulting depletion of WTA re-sensitizes MRSA and MRSE to the lytic effects of β-lactam antibiotics. This suggests that the combination of a tarocin with a suitable -lactam would furnish a useful therapy for MRSA/E based on a safe and familiar drug class. Building on our previous work, the deliverable resulting from the successful completion of the aims in this proposal would be a mechanistically novel, safe, and effective PO administered tarocin/-lactam combination agent with bactericidal activity effective against MDR staphylococci, including MRSA and MRSE, staged to enter IND-enabling studies. Our aims for this proposal are: Aim 1. PCC selection of tarocin potentiator suitable for PO administration. Aim 2. Scale-up and Formulation of tarocin PCC. Aim 3. Selection of optimum β-lactam partner. Aim 4. Efficacy studies using tarocin PCC/optimum β-lactam partner combination. Aim 5. Safety, Metabolism, PK, and non-GLP Toxicology in rat and dog of the tarocin PCC.