{"doi":"10.1101/2024.08.02.606422","title":"An engineered prodrug selectively suppresses β-lactam resistant bacteria in a mixed microbial setting","abstract":"The rise of β-lactam resistance necessitates new strategies to combat bacterial infections. We purposefully engineered the β-lactam prodrug AcephPT to exploit β-lactamase activity to selectively suppress resistant bacteria producing extended-spectrum-β-lactamases (ESBLs). Selective targeting of resistant bacteria requires avoiding interaction with penicillin-binding proteins, the conventional targets of β-lactam antibiotics, while maintaining recognition by ESBLs to activate AcephPT only in resistant cells. Computational approaches provide a rationale for structural modifications to the prodrug to achieve this biased activity. We show AcephPT selectively suppresses gram-negative ESBL-producing bacteria in clonal populations and in mixed microbial cultures, with effective selectivity for both lab strains and clinical isolates expressing ESBLs. Time-course NMR experiments confirm hydrolytic activation of AcephPT exclusively by ESBL-producing bacteria. In mixed microbial cultures, AcephPT suppresses proliferation of ESBL-producing strains while sustaining growth of β-lactamase-non-producing bacteria, highlighting its potential to combat β-lactam resistance while promoting antimicrobial stewardship.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":501812,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9478,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":399111,"name":"Helena Riuró","orcid":"0000-0003-3659-7948","position":1,"is_corresponding":false},{"id":1351432,"name":"César A. Villalobos","orcid":null,"position":2,"is_corresponding":false},{"id":1351433,"name":"Sophia A. Kuhn","orcid":null,"position":3,"is_corresponding":false},{"id":965214,"name":"Katherine He","orcid":"0000-0001-6402-8537","position":4,"is_corresponding":false},{"id":1351434,"name":"Sarah R. Seay","orcid":null,"position":5,"is_corresponding":false},{"id":364221,"name":"Abigail C. Jackson","orcid":"0000-0002-2113-3449","position":6,"is_corresponding":false},{"id":1351086,"name":"Christine M. Suh","orcid":"0009-0008-0912-6132","position":7,"is_corresponding":false},{"id":1351435,"name":"Elena A. Puccio","orcid":null,"position":8,"is_corresponding":false},{"id":393167,"name":"Deverick J. Anderson","orcid":"0000-0001-6882-5496","position":9,"is_corresponding":false},{"id":32929,"name":"Vance G. Fowler","orcid":"0000-0002-8048-0897","position":10,"is_corresponding":false},{"id":302600,"name":"Lingchong You","orcid":"0000-0003-3725-4007","position":11,"is_corresponding":false},{"id":364225,"name":"Katherine J. Franz","orcid":"0000-0002-9015-0998","position":12,"is_corresponding":false},{"id":1164258,"name":"Addison M. Duda","orcid":"0000-0002-8116-4714","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T02:10:15.999370Z","pmid":"39131315","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":[]}