Combating drug-resistant Staphylococcus aureus infection with pathogen-specific positron emission tomography and targeted radionuclide therapy

Staphylococcus aureus (S. aureus) is a major bacterial pathogen and a significant biothreat, representing a leading cause of bacterial mortality worldwide. The challenge is compounded by methicillin-resistant S. aureus (MRSA), a strain resistant to first-line antibiotics, which is associated with a 64% higher mortality rate compared to susceptible strains. Current methods for accurately identifying and localizing occult infections are limited, and there is a critical lack of effective novel treatments for infections that fail to respond to antibiotics. To address this, we pioneered the development of an antimicrobial peptide (AMP)-based radiotheranostic pair for the imaging-guided treatment of S. aureus and MRSA infections. We first screened a library of renowned AMPs for their efficacy against (MR)SA and their suitability for non-invasive, whole-body PET imaging after radiolabeling with Gallium-68. The optimal candidate, [68Ga]QAMP3, demonstrated excellent performance, readily and specifically accumulating in both S. aureus and MRSA infection sites, but not in sterile inflammation or tumors. A pilot first-in-human study confirmed the translatable diagnostic potential and favorable biosafety profile of [68Ga]QAMP3. Furthermore, the corresponding therapeutic agent, [177Lu]QAMP3, effectively reduced bacterial load in rat models of septic arthritis caused by both S. aureus and MRSA following a single systemic administration. Treatment resulted in the complete restoration of joint morphology, comparable to healthy controls. Simultaneously, [68Ga]QAMP3 PET/CT imaging accurately monitored the therapeutic response to both [177Lu]QAMP3 and conventional antibiotic treatment. Finally, molecular dynamics simulations revealed that the stable α-helical conformation of QAMP3 likely confers superior membrane permeability and subsequent internalization into bacterial cells, leading to lethal DNA damage. These findings position [68Ga]/[177Lu]QAMP3 as an innovative theranostic pair for the rapid diagnosis and effective treatment of MRSA infections. This study also paves the way for developing new radio-antibiotics with mechanisms of action that can circumvent conventional antibiotic resistance.