Amicidins: Novel synthetic biologics for prevention and treatment of wound infections in trauma and surgery
Michael Bevilacqua, MD, PhD, Amicrobe, Inc.; Carl Edwards, III, Amicrobe, Inc.; Shalyn Lane, Amicrobe, Inc.; Daniel Huang, Amicrobe, Inc.; Timothy Deming, PhD, University of California at Los Angeles; Joseph Solomkin, MD, Amicrobe, Inc.
Background:Surgical antisepsis is a growing challenge. Neither systemic antibiotics, nor directly-applied antibiotics / antiseptics are adequate to address the rise of aggressive and antibiotic-resistant microbes. Amicidins are a new class of directly-applied biologics that combine broad antimicrobial activity with beneficial physical properties to enhance intra-wound performance. Amicidin-α combines microbicidal activity with persisting barrier properties to prevent infection. Amicidin-β combines microbicidal activity with superior anti-biofilm properties to treat infections, especially those involving foreign bodies, such as orthopedic hardware.
Hypothesis:Amicidins are highly effective as directly applied antimicrobials at concentrations that cause little, if any, tissue toxicity.
Methods:Synthesized using “one pot” living polymerization, Amicidins are greater than 100 amino acids in length, arranged as one cationic segment (lysines) and one hydrophobic segment (leucines). Antimicrobial activity is measured in 5 and 60 minute time-kill assays. Microbial barrier and anti-biofilm properties are measured using porcine skin ex vivo, as well as in standard in vitro assays. Porcine open wound and rodent closed wound with foreign body (mesh) models assess activity in vivo. Preliminary safety studies include dermal irritation and sensitization, oral toxicity, and intraperitoneal toxicity.
Results:In 5 and 60 min time-kills, Amicidin-α and Amicidin-β at 10 to 100 μg/mL show 99.9-99.9999% reductions in colony forming units (CFU) of Gram-positive and Gram-negative bacteria, as well as yeast, including multidrug-resistant strains. At higher concentrations, Amicidin-α forms viscous solutions and hydrogels that are microbial barriers on porcine skin ex vivo, as well as porcine full-thickness open wounds and rodent closed wounds with foreign body in vivo. Pretreatment prior to microbial inoculation results in multi-log reductions of tissue- and foreign body-associated pathogens. Amicidin-β demonstrates rapid (20 min) eradication of P. aeruginosa biofilms in vitro. It also causes multi-log reduction in CFU of MRSA and P. aeruginosa in the rodent closed wound model with a single application 15 min after microbial inoculation, assessed at 48h. Preliminary safety studies show a favorable profile for local application.
Conclusions:Amicidins demonstrate rapid and potent killing of clinically relevant microorganisms with excellent tissue compatibility. These data support progress to a first-in-man clinical trial.