Vancomycin-Teixobactin Conjugates

About This Grant

Project Summary / Abstract: Vancomycin-Teixobactin Conjugates Antibiotic resistance is a growing public health crisis, with Gram-positive bacterial infections—including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE)—causing over 2.8 million infections and 35,000 deaths annually in the U.S. Vancomycin has been a mainstay antibiotic for treating Gram-positive infections, but resistance mechanisms such as the D-Ala-D-Lac modification in VRE significantly reduce its efficacy. Teixobactin, a promising antibiotic targeting the pyrophosphate group of lipid II, has potent activity but suffers from poor solubility and aggregation, hindering its clinical translation. This proposal aims to develop novel vancomycin-teixobactin conjugates that combine the strengths of both antibiotics to overcome vancomycin resistance while addressing teixobactin’s formulation challenges. The central hypothesis is that linking vancomycin to the minimal teixobactin pharmacophore will create conjugates with dual lipid II binding capability, restoring activity against resistant Gram-positive pathogens. The proposed research will: 1. Optimize vancomycin-teixobactin conjugates through structure-activity relationship (SAR) studies by modifying key functional groups, linker chemistry, and teixobactin residues to maximize antibacterial activity while minimizing cytotoxicity. 2. Evaluate the in vitro efficacy of lead conjugates against clinically relevant strains of MRSA, VRE, and VISA, and conduct time-kill and resistance studies to identify bactericidal compounds with low resistance potential. 3. Assess in vivo efficacy and pharmacokinetics (PK) using a neutropenic mouse thigh infection model, preliminary ADME (Absorption, Distribution, Metabolism, and Excretion) profiling, and single-dose PK studies, in order to identify a lead compound suitable for further preclinical development. This research is innovative because it leverages synergistic antibiotic targeting by combining vancomycin’s D-Ala-D-Ala binding with teixobactin’s pyrophosphate targeting, thereby restoring vancomycin’s efficacy against resistant pathogens. The successful completion of this study will identify a lead vancomycin-teixobactin conjugate with strong in vitro and in vivo activity, setting the foundation for future preclinical and clinical development. This work has the potential to establish a next-generation antibiotic strategy for treating multidrug- resistant Gram-positive infections, ultimately improving patient outcomes and public health.