A Modular Nanoantibiotic Platform for Treatment Against Aerosolized Biothreat Agents

The goal of this SBIR Sequential Phase II project is to develop a novel nanoantibiotics (nAbts) platform for designing and synthesizing nanocarriers able to effectively deliver antimicrobial peptides (AMPs) to the lung to treat pulmonary infections from aerosolized biothreat agents. Aerosol deployment of a biological select agent is one of the nation’s greatest bioterrorism risks because infectious material can be widely dispersed and can cause severe pulmonary infection with associated morbidity and mortality. Burkholderia pseudomallei, the causative agent for melioidosis and a Tier 1 select agent, is of particular concern because of its high rate of infectivity via aerosols, resistance to many common antibiotics, and history within foreign biological weapons programs. We will assess effectiveness of the proposed nAbts platform on B. thailandensis strain E264, a BSL-1 surrogate for B. pseudomallei. The rapid spread of multidrug antimicrobial resistance (AMR) among Gram-negative pathogens threatens to eliminate the effectiveness of traditional antibiotics, therefore new types of antimicrobial agents that are highly potent and able to sidestep bacterial resistance are urgently needed. We will therefore employ AMPs as primary therapeutic agents. AMPs exhibit broad-spectrum activity against a variety of pathogens and avoid promotion of bacterial resistance, making them attractive candidates for clinical development. We will test in vitro several AMPs for efficacy against B. thailandensis and select three AMPs for subsequent experimentation. To improve their bioactivity and bactericidal effectiveness, we have designed a novel nanocarrier, P-AM1, that concentrates AMPs for delivery to the lung. We will synthesize and characterize P-AM1 variants containing various combinations of selected AMPs, then test and optimize their antimicrobial activity in vitro against B. thailandensis. Finally, we will use a nebulized formulation of the best P-AM1 variant and test its efficacy in a B. thailandensis murine challenge model. At the conclusion of the investigation, we expect to have identified a lead P-AM1 candidate for treatment of B. pseudomallei that is ready for preclinical development in nonhuman primates.