Development of Novel Polyacrylamides for Use as Broad-spectrum Antibiotics

Stanford scientists have developed novel polyacrylamide-based copolymers that exhibit antimicrobial activity against both Gram-negative and Gram-positive bacteria through a membrane disruption mechanism. This approach of using polyacrylamides to selectively disrupt bacterial membranes as a killing mechanism is able to circumvent known antimicrobial resistance pathways. Consequently, this technology could play a significant role in addressing the growing antibiotic resistance crisis.

Antimicrobial resistance is a critical global health threat, with antibiotic-resistant pathogens projected to cause over ten million annual deaths by 2050. Despite this crisis, the development of new antibiotic classes has stagnated while resistant bacteria rapidly emerge. Common resistance mechanisms include drug uptake inhibition, drug target modification, and enhanced drug efflux. Broad-spectrum antibiotics that disrupt bacterial membranes are an attractive solution that could potentially bypass these mechanisms, but existing compounds face challenges in synthesis, scalability, toxicity, and/or stability. Polyacrylamides offer promise in addressing these issues, with inexpensive scalable synthesis and high chemical stability enabling potential global distribution without cold chain requirements.

The synthesized polyacrylamide compounds demonstrated significant antimicrobial activity against both Gram-negative (E. coli and K. pneumoniae) and Gram-positive (S. aureus and E. faecium) bacteria, with minimum inhibitory concentrations (MICs) approaching clinically relevant levels. Importantly, these polymers exhibit selectivity in killing bacteria over lysing red blood cells, with a 50% hemolytic concentration (HC50) more than twenty times higher than their MICs. They exhibit antimicrobial activity through a membrane-disruption mechanism that is able to delay or prevent the development of resistance in E. coli over 15 passages. They also improve the potency of existing antibiotics and prevent or delay the development of resistance to existing antibiotics when delivered in a combination therapy. The broad-spectrum activity of these polyacrylamides, combined with their membrane-disrupting mechanism, indicates effectiveness against bacterial infections while circumventing common resistance mechanisms. This demonstrates the potential of these compounds to replace or rehabilitate existing antibiotics.

Figure

Stage of Development
Preclinical: in-vitro data
Continued research: Expanding library of novel polyacrylamides to screen for high antimicrobial activity and low hemolytic activity. In addition, assessment of stability, efficacy and safety in a rodent model of pneumonia