{"doi":"10.1021/acsinfecdis.2c00640","title":"Optimization of Host Cell-Compatible, Antimicrobial Peptides Effective against Biofilms and Clinical Isolates of Drug-Resistant Bacteria","abstract":"High Resolution Image Download MS PowerPoint Slide 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.","journal":"ACS Infectious Diseases","year":2023,"id":344121,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9481,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1083052,"name":"Robert J. Hart","orcid":null,"position":1,"is_corresponding":false},{"id":876618,"name":"Anabel Soldano","orcid":null,"position":2,"is_corresponding":false},{"id":110467,"name":"Charles H. Chen","orcid":"0000-0001-7695-5215","position":3,"is_corresponding":false},{"id":484402,"name":"Shantanu Guha","orcid":"0000-0002-7027-0183","position":4,"is_corresponding":false},{"id":473074,"name":"Joseph P. Hoffmann","orcid":"0000-0001-8300-7782","position":5,"is_corresponding":false},{"id":1083053,"name":"Kalen M. Hall","orcid":null,"position":6,"is_corresponding":false},{"id":914355,"name":"Leisheng Sun","orcid":"0000-0003-0358-1421","position":7,"is_corresponding":false},{"id":1082481,"name":"Benjamin J. Nelson","orcid":"0000-0001-8529-4850","position":8,"is_corresponding":false},{"id":61655,"name":"Timothy K. Lu","orcid":"0000-0002-3918-8923","position":9,"is_corresponding":false},{"id":246970,"name":"Jay K. Kolls","orcid":"0000-0001-5151-6304","position":10,"is_corresponding":false},{"id":498762,"name":"Mario Rivera","orcid":"0000-0002-5692-5497","position":11,"is_corresponding":false},{"id":340249,"name":"Lisa A. Morici","orcid":"0000-0002-4799-4941","position":12,"is_corresponding":false},{"id":336459,"name":"William C. Wimley","orcid":"0000-0003-2967-5186","position":13,"is_corresponding":false},{"id":484404,"name":"Jenisha Ghimire","orcid":"0000-0002-3097-4194","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T01:11:30.951510Z","pmid":"36961222","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}