{"doi":"10.3389/fmicb.2025.1605813","title":"Synergistic action between peptide-neomycin conjugates and polymyxin B against multidrug-resistant gram-negative pathogens","abstract":"Globally, it is predicted that by 2050, 10 million people will die annually because of infections with drug-resistant bacteria. Since antibacterial agents with novel mechanisms of action have not been developed in the past 30 years, there has been a surge of interest in combination therapies using existing drugs. The combination of aminoglycosides and colistin is often used to treat pneumonia caused by multidrug-resistant bacteria. The goal of this study is to investigate the relationship between the antibacterial activity of a peptide-neomycin library and polymyxin B in extensively drug-resistant and pandrug-resistant bacteria. The peptide-neomycin library contained conjugates with one or two amino acids linked to neomycin, rendering them unsuitable substrates for aminoglycoside-modifying enzymes. Neomycin- susceptible and neomycin-resistant members of Acinetobacter baumannii, Klebsiella pneumoniae , and Pseudomonas aeruginosa were screened for synergy with polymyxin B using two-way checkerboard and time-kill methods. Most A. baumannii strains are resistant to amikacin, gentamicin, tobramycin, and plazomicin, and approximately half are susceptible to neomycin. P. aeruginosa strains have a similar resistance profile but was more susceptible to plazomicin. K. pneumoniae strains are most susceptible to a wide variety of aminoglycosides. Bacteria challenged with a combination of neomycin, other aminoglycosides, and polymyxin B exhibited an additive to indifferent relationship, whereas synergy was found with several neomycin-peptide conjugates containing cysteine, arginine, or tryptophan, lowering the minimal inhibitory concentration for the peptide-neomycin conjugate by 8-64-fold and polymyxin B by 2-8-fold. Cysteine, arginine, or tryptophan conjugates were the most effective against A. baumannii and K. pneumoniae carrying a 16S rRNA methyltransferase gene and a pandrug-resistant P. aeruginosa strain. Resistance to the combination of R-, C-, or RC-NEO conjugates and PB did not develop over a 14-day period in neomycin-susceptible strains of A. baumannii, K. pneumoniae , and P. aeruginosa . Based on this survey of the peptide-neomycin library, circumvention of aminoglycoside-modifying enzymes and alluding to bacterial resistance is an important step toward the design and development of peptide aminoglycoside-based motifs for antimicrobial drug development.","journal":"Frontiers in Microbiology","year":2025,"id":521816,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9468,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":731032,"name":"Liuwei Jiang","orcid":"0000-0001-6178-4505","position":1,"is_corresponding":false},{"id":1288790,"name":"Alain Simplice Leutou","orcid":"0000-0002-2594-9007","position":2,"is_corresponding":false},{"id":523481,"name":"Dev P. Arya","orcid":"0000-0001-5873-1066","position":3,"is_corresponding":false},{"id":1289262,"name":"Sandra P. Story","orcid":null,"position":0,"is_corresponding":true}],"reference_count":100,"raw_metadata":null,"created_at":"2026-07-19T02:49:49.198144Z","pmid":"40851856","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":[]}