Optimization of Host Cell-Compatible, Antimicrobial Peptides Effective against Biofilms and Clinical Isolates of Drug-Resistant Bacteria

• Autores: Ghimire, Jenisha; Hart, Robert J.; Soldano, Anabel; Chen, Charles H.; Guha, Shantanu; Hoffmann, Joseph P.; Hall, Kalen M.; Sun, Leisheng; Nelson, Benjamin J.; Lu, Timothy K.; Kolls, Jay K.; Rivera, Mario; Morici, Lisa A.; Wimley, William C.
• Año de publicación: 2023
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: ANTIBIOTIC; ANTIMICROBIAL PEPTIDE; DRUG RESISTANCE; MOLECULAR EVOLUTION
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Here, we describe the continued synthetic molecular evolution of a lineage of host-compatible antimicrobial peptides (AMP) intended for the treatment of wounds infected with drug-resistant, biofilm-forming bacteria. The peptides tested are variants of an evolved AMP called d-amino acid CONsensus with Glycine Absent (d-CONGA), which has excellent antimicrobial activities in vitro and in vivo. In this newest generation of rational d-CONGA variants, we tested multiple sequence-structure-function hypotheses that had not been tested in previous generations. Many of the peptide variants have lower antibacterial activity against Gram-positive or Gram-negative pathogens, especially variants that have altered hydrophobicity, secondary structure potential, or spatial distribution of charged and hydrophobic residues. Thus, d-CONGA is generally well tuned for antimicrobial activity. However, we identified a variant, d-CONGA-Q7, with a polar glutamine inserted into the middle of the sequence, that has higher activity against both planktonic and biofilm-forming bacteria as well as lower cytotoxicity against human fibroblasts. Against clinical isolates of Klebsiella pneumoniae, innate resistance to d-CONGA was surprisingly common despite a lack of inducible resistance in Pseudomonas aeruginosa reported previously. Yet, these same isolates were susceptible to d-CONGA-Q7. d-CONGA-Q7 is much less vulnerable to AMP resistance in Gram-negative bacteria than its predecessor. Consistent with the spirit of synthetic molecular evolution, d-CONGA-Q7 achieved a critical gain-of-function and has a significantly better activity profile.
Fil: Ghimire, Jenisha. University of Tulane; Estados Unidos
Fil: Hart, Robert J.. University of Tulane; Estados Unidos
Fil: Soldano, Anabel. Louisiana Tech University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Agrobiotecnología del Litoral. Universidad Nacional del Litoral. Instituto de Agrobiotecnología del Litoral; Argentina
Fil: Chen, Charles H.. Massachusetts Institute of Technology; Estados Unidos
Fil: Guha, Shantanu. University of Tulane; Estados Unidos
Fil: Hoffmann, Joseph P.. University of Tulane; Estados Unidos
Fil: Hall, Kalen M.. University of Tulane; Estados Unidos
Fil: Sun, Leisheng. University of Tulane; Estados Unidos
Fil: Nelson, Benjamin J.. University of Tulane; Estados Unidos
Fil: Lu, Timothy K.. Massachusetts Institute of Technology; Estados Unidos
Fil: Kolls, Jay K.. University of Tulane; Estados Unidos
Fil: Rivera, Mario. State University of Louisiana; Estados Unidos
Fil: Morici, Lisa A.. University of Tulane; Estados Unidos
Fil: Wimley, William C.. University of Tulane; Estados Unidos