{"doi":"10.3389/fbrio.2023.1253097","title":"Relationship between cell envelope ultrastructure and the antibacterial properties of a novel hydrophobic eumelanin-inspired derivative","abstract":"Introduction Unique impermeability properties of the gram-negative outer cell envelope typically render these organisms intrinsically resistant to hydrophobic antibacterial compounds. Eumelanin-inspired indoylenephenyleneethynylene (EIPE) compounds possess scaffolding to which functional groups were attached to potentially provide antibacterial properties in the forms of hydrophilic (EIPE-HCl) and hydrophobic (EIPE-1) derivatives. Methods Standardized disk agar diffusion and microbroth dilution bioassays were employed to assess the susceptibility of disparate gram-negative and gram-positive bacterial pathogens to the two compounds. EIPE-1 mechanisms of action and intrinsic resistance were further investigated turbidimetrically in batch cultures with the aid of the gram-negative outer membrane permeabilizer compound 48/80. Results Hydrophobic derivative EIPE-1 exhibited a gram-positive antibacterial spectrum, while hydrophilic derivative EIPE-HCl possessed no antibacterial properties. EIPE-1 exhibited minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values below 2.0 µg/mL against all gram-positive bacteria, including two methicillin-resistant strains. In contrast, MIC/MBC values greater than 128 µg/mL were obtained for all gram-negative bacteria examined. Susceptibility of two strains of the strict anaerobe Clostridioides difficile indicated the EIPE-1 mechanism of action does not require molecular oxygen. Turbidimetric growth curves revealed EIPE-1 induced rapid bacteriolysis of Bacillus subtilis ATCC 6633, thereby suggesting a membrane-directed modality. Lastly, the outer membrane permeabilizer compound 48/80 failed to markedly sensitize any of three phylogenetically disparate gram-negative organisms to EIPE-1. Conclusion These data suggest that the hydrophobic melanin-inspired derivative EIPE-1 inhibits gram-positive bacteria in a cytoplasmic membrane-directed manner independent of oxygen. Moreover, a secondary mechanism may function concomitantly with outer membrane exclusionary properties to underly the intrinsic resistance of gram-negative pathogens.","journal":"Frontiers in Bacteriology","year":2023,"id":377417,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9473,"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":1141128,"name":"Katherine Nehmzow","orcid":null,"position":1,"is_corresponding":false},{"id":526524,"name":"Martha A. Essandoh","orcid":null,"position":2,"is_corresponding":false},{"id":1141129,"name":"Mohammad Ebqa’ai","orcid":null,"position":3,"is_corresponding":false},{"id":731349,"name":"Toby L. Nelson","orcid":"0000-0001-5549-6072","position":4,"is_corresponding":false},{"id":962314,"name":"Erika I. Lutter","orcid":"0000-0002-1953-2467","position":5,"is_corresponding":false},{"id":919577,"name":"Gabriel A. Cook","orcid":"0000-0002-3413-8361","position":6,"is_corresponding":false},{"id":1100419,"name":"Franklin R. Champlin","orcid":"0000-0002-9861-8903","position":7,"is_corresponding":false},{"id":638744,"name":"Daniel Reed","orcid":"0000-0003-2965-4342","position":0,"is_corresponding":true}],"reference_count":16,"raw_metadata":null,"created_at":"2026-07-19T01:16:36.370283Z","pmid":null,"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":[]}