(660a) Novel Nanoparticle Antimicrobial Approaches for MDR and Intracellular Infections

The rising prevalence of antibiotic resistant pathogens and their rapid ability to adapt highlights the need for a streamlined, rapid response system for emerging infectious diseases. To address this, I have developed novel antimicrobial therapeutics including nanoparticles and anti-sense therapeutics to address multi-drug resistant bacteria and intracellular infections. Within my work I have utilized superoxide producing, light-activated nanoparticles to treat an intracellular infection of Salmonella in pre-osteoblast (bone) cells. This strategy utilizes stimuli-activated nanoparticles that are precisely tuned to induce a precise and toxic response at the target.

Additionally, within my research I worked to develop the Facile Accelerated Specific Therapeutic (FAST) platform which generates sequence-specific peptide nucleic acid (PNA) therapeutics against infectious diseases in under a week. Here we showcase its efficacy against patient isolated multi-drug resistant (MDR) bacteria. PNAs are designed against lab strain versions of pathogens to target clinical isolates at a high success rate (82%) using our Bioinformatics toolbox, an automated workflow analyzing a user-defined set of genes for PNA candidacy. Nine different essential and non-essential PNAs were tested against five different clinical isolates: carbapenem-resistant Escherichia coli, extended-spectrum beta-lactamase Klebsiella pneumoniae, New Delhi Metallo-beta-lactamase-1 carrying Klebsiella pneumoniae, and MDR Salmonella enterica. PNA treatment showed growth inhibition in 82% of treatments with nearly 18% of treatments having greater than 97% growth inhibition. Additionally, we developed a novel bacterial delivery strategy for enhancing PNA’s transport into host cells via a bacterial carrier expressing the Type III secretion system (T3SS) combined with a holin-endolysin kill switch. This delivery and release method was successful at treating an intracellular infection of Salmonella enterica serovar Typhimurium in HeLa cells and an ESBL KPN infection in RAW264.7 host cells. The FAST platform is an adaptable tool for rapid response that can be easily altered to target numerous infectious diseases.