Journal Article

The heme oxygenase-1 metalloporphyrin inhibitor stannsoporfin enhances the bactericidal activity of a novel regimen for multidrug-resistant tuberculosis in a murine model

Garcia, Andrew, Neupane, Pranita, Fotouhi, Nader, Serbina, Natalya, Quijada, Darla, Ayeh, Samuel, Castillo, Jennie Ruelas, Karanika, Styliani, Krug, Stefanie, Yilma, Addis, Costa, Diego L, Karakousis, Petros C, Sher, Alan

2023

Overview

Multidrug-resistant (MDR) (Mtb) poses significant challenges to global tuberculosis (TB) control efforts. Host-directed therapies (HDT) offer a novel approach for TB treatment by enhancing immune-mediated clearance of Mtb. Prior preclinical studies found that 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 5 mg/kg reduced mean lung bacillary burden by an additional 0.69 log (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 10 mg/kg reduced lung bacterial burdens to 0.71 ± 0.23 log CFU, 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.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Animal models / Bactericidal activity / Body weight / CD38 antigen / Drug resistance / Heme oxygenase (decyclizing) / Histology / Immune clearance / Inflammation / Lungs / Macrophages / Microbiology / Multidrug resistance / Protoporphyrin / Protoporphyrin IX / Tuberculosis