1. Academic Validation
  2. Preclinical Evaluation of Inhalational Spectinamide-1599 Therapy against Tuberculosis

Preclinical Evaluation of Inhalational Spectinamide-1599 Therapy against Tuberculosis

  • ACS Infect Dis. 2021 Oct 8;7(10):2850-2863. doi: 10.1021/acsinfecdis.1c00213.
Mercedes Gonzalez-Juarrero 1 Pradeep B Lukka 2 Santosh Wagh 2 Amanda Walz 1 Jennifer Arab 1 Camron Pearce 1 Zohaib Ali 1 Josiah T Ryman 2 Keyur Parmar 2 Zaid Temrikar 2 Juan Munoz-Gutierrez 1 Gregory T Robertson 1 Jiuyu Liu 3 Anne J Lenaerts 1 Charles Daley 4 Richard E Lee 3 Miriam Braunstein 5 Anthony J Hickey 6 Bernd Meibohm 2
Affiliations

Affiliations

  • 1 Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523, United States.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 3 Department of Chemical Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 4 Division of Mycobacterial and Respiratory Infections, National Jewish Health, Denver, Colorado 80206, United States.
  • 5 Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 6 Discovery Science and Technology, RTI International, RTP, Durham, North Carolina 27709, United States.
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 log10 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.

Keywords

aerosol; animal models; pharmacokinetics; spectinamides; tuberculosis.

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