Preclinical Evaluation of Inhalational Spectinamide-1599 Therapy against Tuberculosis

Abstract

The lengthy treatment time for tuberculosis (TB) is a primary cause for the emergence of multidrug resistant tuberculosis (MDR-TB). One approach to improve TB therapy is to develop an inhalational TB therapy that when administered in combination with oral TB drugs eases and shortens treatment. Spectinamides are new semisynthetic analogues of spectinomycin with excellent activity against Mycobacterium tuberculosis (Mtb), including MDR and XDR Mtb strains. Spectinamide-1599 was chosen as a promising candidate for development of inhalational therapy. Using the murine TB model and intrapulmonary aerosol delivery of spectinamide-1599, we characterized the pharmacokinetics and efficacy of this therapy in BALB/c and C3HeB/FeJ mice infected with the Mtb Erdman strain. As expected, spectinamide-1599 exhibited dose-dependent exposure in plasma, lungs, and ELF, but exposure ratios between lung and plasma were 12−40 times higher for intrapulmonary compared to intravenous or subcutaneous administration. In chronically infected BALB/c mice, low doses (10 mg/kg) of spectinamide-1599 when administered thrice weekly for two months provide efficacy similar to that of higher doses (50−100 mg/kg) after one month of therapy. In the C3HeB/FeJ TB model, intrapulmonary aerosol delivery of spectinamide-1599 (50 mg/kg) or oral pyrazinamide (150 mg/kg) had limited or no efficacy in monotherapy, but when both drugs were given in combination, a synergistic effect with superior bacterial reduction of >1.8 log 10 CFU was observed. Throughout the up to eight-week treatment period, intrapulmonary therapy was well-tolerated without any overt toxicity. Overall, these results strongly support the further development of intrapulmonary spectinamide-1599 as a combination partner for anti-TB therapy.

A Modified BPaL Regimen for Tuberculosis Treatment replaces Linezolid with Inhaled Spectinamides

“…We used two preclinical chronic TB murine efficacy models (30)(31)(32) to investigate BPa, BPaL and BPaS, for efficacy and any associated AEs during the course of 4weeks of treatment. Based on the diversity of outcomes observed during human TB disease (22) and as no single animal model recapitulates the wide spectrum of human TB pathology (33), we chose the Balb/c and C3HeB/FeJ murine TB models. The Balb/c chronic TB model is representative of a long-term Mtb chronic infection that develops homogenous lung granulomatous lesions restraining the bacilli within intracellular compartments (34) of macrophages and foamy macrophages.…”

Natural products and their analogues acting against Mycobacterium tuberculosis: A recent update

“…At the same time, in the C3HeB/FeJ TB model, aerosol delivery of spectinamide‐1599 (50 mg/kg) or oral pyrazinamide (150 mg/kg) showed no efficacy as monotherapy. Still, when both drugs were combined, a synergistic effect with a superior bacterial reduction of >1.8 log 10 CFU was observed (Gonzalez‐Juarrero et al, 2021). This finding suggests spectinamide‐1599 could be used in combination therapy with first‐line drug pyrazinamide for TB treatment.…”

“Upcycling” known molecules and targets for drug-resistant TB

“…The semisynthetic spectinamides, on the other hand, demonstrate improved selectivity as well as more potent anti-M.tb activity by avoiding efflux through the M.tb efflux pump Rv1258c. In a remarkable medicinal chemistry effort, Lee and colleagues optimized the series to avoid the Rv1258c efflux pump resulting in leads that demonstrate significant activity in acute and chronic mouse models of TB and contribute to combinations of TB drugs ( Lee et al., 2014 ; Bruhn et al., 2015 ; Gonzalez-Juarrero et al., 2021 ).…”