Modified poly(L-lysine)-based structures as novel antimicrobials for diabetic foot infections, an study.

Wound infections occur as sequelae to skin trauma and cause significant hospitalizations, morbidity and mortality. Skin traumas arise more frequently in those with diabetes or cardiovascular disease and in these settings, may be chronic with poorer outcomes including lower limb amputation. Treatment of chronic wound infection is challenging due to antibiotic resistance and biofilm formation by bacteria including and which are among the most frequent causative pathogens. Managing these challenging infections requires new molecules and modalities. We evaluated antimicrobial and anti-biofilm activity of star-shaped poly(L-lysine) (PLL) polymers against and strains and clinical isolates recovered from wounds including diabetic foot wounds (DFW) in a Dublin Hospital in 2019. A star-shaped PLL polypeptide series, specifically G2(8)PLL , G3(16)PLL , G4(32)PLL with variation in polypeptide chain length and arm-multiplicity, were compared to a linear peptide, PLL with equivalent number of lysine residues. All PLLs, including the linear polypeptide, were bactericidal at 1μM against 25923 and PAO1, with log reduction in colony forming units/ml between 2.7-3.6. PLL demonstrated similar killing potency against 20 and five clinical isolates from DFW, mean log reductions: 3.04 ± 0.16 and 3.96 ± 0.82 respectively after 1 hour incubation. Potent anti-biofilm activity was demonstrated against 25923 but for clinical isolates, low to moderate loss of biofilm viability was shown using PLL and G3(16)PLL at 50 μM ( ) and 200 μM ( ) with high inter-isolate variability In the star-shaped architecture, antimicrobial activity was retained with incorporation of 5-mer hydrophobic amino-acid modifications to the arms of the polypeptides (series G3(16)PLL -coPLT , G3(16)PLL -coPLI , G3(16)PLL -coPLP ). These polypeptides offer structural flexibility for clinical applications and have potential for further development, particularly in the setting of diabetic foot and other chronic wound infections.