{"doi":"10.1128/aac.01043-23","title":"The heme oxygenase-1 metalloporphyrin inhibitor stannsoporfin enhances the bactericidal activity of a novel regimen for multidrug-resistant tuberculosis in a murine model","abstract":"ABSTRACT Multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) poses significant challenges to global tuberculosis (TB) control efforts. Host-directed therapies (HDTs) offer a novel approach to TB treatment by enhancing immune-mediated clearance of Mtb. Prior preclinical studies found that the inhibition of heme oxygenase-1 (HO-1), an enzyme involved in heme metabolism, with tin-protoporphyrin IX (SnPP) significantly reduced mouse lung bacillary burden when co-administered with the first-line antitubercular regimen. Here, we evaluated the adjunctive HDT activity of a novel HO-1 inhibitor, stannsoporfin (SnMP), in combination with a novel MDR-TB regimen comprising a next-generation diarylquinoline, TBAJ-876 (S), pretomanid (Pa), and a new oxazolidinone, TBI-223 (O) (collectively, SPaO), in Mtb-infected BALB/c mice. After 4 weeks of treatment, SPaO + SnMP 5mg/kg reduced mean lung bacillary burden by an additional 0.69 log 10 ( P = 0.01) relative to SPaO alone. As early as 2 weeks post-treatment initiation, SnMP adjunctive therapy differentially altered the expression of pro-inflammatory cytokine genes and CD38, a marker of M1 macrophages. Next, we evaluated the sterilizing potential of SnMP adjunctive therapy in a mouse model of microbiological relapse. After 6 weeks of treatment, SPaO + SnMP 10mg/kg reduced lung bacterial burdens to 0.71 ± 0.23 log 10 colony-forming units (CFUs), a 0.78 log-fold greater decrease in lung CFU compared to SpaO alone ( P = 0.005). However, adjunctive SnMP did not reduce microbiological relapse rates after 5 or 6 weeks of treatment. SnMP was well tolerated and did not significantly alter gross or histological lung pathology. SnMP is a promising HDT candidate requiring further study in combination with regimens for drug-resistant TB.","journal":"Antimicrobial Agents and Chemotherapy","year":2023,"id":363317,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"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":659445,"name":"Pranita Neupane","orcid":null,"position":1,"is_corresponding":false},{"id":311495,"name":"Styliani Karanika","orcid":"0000-0003-2387-6075","position":2,"is_corresponding":false},{"id":644498,"name":"Stefanie Krug","orcid":"0000-0001-6390-3184","position":3,"is_corresponding":false},{"id":503686,"name":"Darla Quijada","orcid":null,"position":4,"is_corresponding":false},{"id":1117334,"name":"Andrew Garcia","orcid":"0000-0003-1670-9818","position":5,"is_corresponding":false},{"id":631216,"name":"Samuel K. Ayeh","orcid":null,"position":6,"is_corresponding":false},{"id":1117775,"name":"Addis Yilma","orcid":null,"position":7,"is_corresponding":false},{"id":467111,"name":"Diego L. Costa","orcid":"0000-0002-9440-2814","position":8,"is_corresponding":false},{"id":330710,"name":"Alan Sher","orcid":"0000-0001-7053-2895","position":9,"is_corresponding":false},{"id":656134,"name":"Nader Fotouhi","orcid":null,"position":10,"is_corresponding":false},{"id":1117335,"name":"Natalya V. Serbina","orcid":"0009-0007-2303-9468","position":11,"is_corresponding":false},{"id":333926,"name":"Petros C. Karakousis","orcid":"0000-0003-1338-9206","position":12,"is_corresponding":false},{"id":331270,"name":"Jennie Ruelas Castillo","orcid":"0000-0003-4570-205X","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T01:14:28.054440Z","pmid":"38132181","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":[]}