{"doi":"10.1128/aac.00127-25","title":"Combinations comprising dual β-lactams and a β-lactamase inhibitor achieve optimal synergistic inhibition of <i>Mycobacterium abscessus</i> growth","abstract":"ABSTRACT The historical model, which posits that β-lactams inhibit bacterial growth while β-lactamase inhibitors (BLIs) merely protect β-lactams from enzymatic degradation, fails to fully explain their activity against Mycobacterium abscessus ( Mab ). This study demonstrates that synergistic effects extend beyond the traditional one β-lactam + one BLI paradigm, refuting the oversimplified mechanistic framework. First, β-lactam-based BLIs such as clavulanic acid, sulbactam, and tazobactam exhibit intrinsic antibacterial activity against Mab . These agents synergized not only with β-lactams but also with one another, undermining their historical classification as mere β-lactamase inhibitors. The data indicate that their activity is not limited to inhibiting β-lactamases but extends to directly targeting critical bacterial processes. Second, dual β-lactam combinations exhibit synergism against Mab even in the absence of BLIs. For example, despite being rapidly hydrolyzed by the native β-lactamase Bla Mab , amoxicillin demonstrates strong synergism with β-lactams such as imipenem or ceftaroline. This suggests that the second β-lactam either acts as a functional BLI surrogate or targets complementary pathways. Supporting this, experiments using penicillin- and carbapenem-based probes revealed that β-lactams bind to multiple Mab proteins simultaneously, reinforcing the idea that their synergy arises from targeting complementary essential proteins. Finally, triple combinations comprising dual β-lactam and one BLI, such as amoxicillin + ceftaroline + avibactam, achieved very high synergy, underscoring the complementary roles of dual β-lactams and BLIs. The evidence in this study necessitates a revised model that can more accurately explain the activities of β-lactams and BLIs and underscores the potential for optimizing β-lactam/BLI regimens against Mab .","journal":"Antimicrobial Agents and Chemotherapy","year":2025,"id":572342,"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":0.9503,"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":107348,"name":"Yi Xie","orcid":"0000-0003-4251-6219","position":1,"is_corresponding":false},{"id":908571,"name":"Chandra M. Panthi","orcid":null,"position":2,"is_corresponding":false},{"id":511526,"name":"Kaylyn L. Devlin","orcid":"0000-0001-5842-0591","position":3,"is_corresponding":false},{"id":998520,"name":"Kimberly E. Beatty","orcid":"0000-0002-2303-8779","position":4,"is_corresponding":false},{"id":299601,"name":"Gyanu Lamichhane","orcid":"0000-0002-2214-0114","position":5,"is_corresponding":false},{"id":337602,"name":"Binayak Rimal","orcid":"0000-0003-3457-4523","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:57:23.653298Z","pmid":"40810695","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":[]}