Drug distribution and efficacy of the DprE1 inhibitor BTZ-043 in the C3HeB/FeJ mouse tuberculosis model.

Autor:	Ramey ME; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado, USA., Kaya F; Center for Discovery and Innovation, Hackensack Meridian School of Medicine , Nutley, New Jersey, USA., Bauman AA; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado, USA., Massoudi LM; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado, USA., Sarathy JP; Center for Discovery and Innovation, Hackensack Meridian School of Medicine , Nutley, New Jersey, USA., Zimmerman MD; Center for Discovery and Innovation, Hackensack Meridian School of Medicine , Nutley, New Jersey, USA., Scott DWL; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado, USA., Job AM; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado, USA., Miller-Dawson JA; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado, USA., Podell BK; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado, USA., Lyons MA; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado, USA., Dartois V; Center for Discovery and Innovation, Hackensack Meridian School of Medicine , Nutley, New Jersey, USA., Lenaerts AJ; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado, USA., Robertson GT; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado, USA.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2023 Nov 15; Vol. 67 (11), pp. e0059723. Date of Electronic Publication: 2023 Oct 04.
DOI:	10.1128/aac.00597-23
Abstrakt:	BTZ-043, a suicide inhibitor of the Mycobacterium tuberculosis cell wall synthesis decaprenylphosphoryl-beta-D-ribose 2' epimerase, is under clinical development as a potential new anti-tuberculosis agent. BTZ-043 is potent and bactericidal in vitro but has limited activity against non-growing bacilli in rabbit caseum. To better understand its behavior in vivo , BTZ-043 was evaluated for efficacy and spatial drug distribution as a single agent in the C3HeB/FeJ mouse model presenting with caseous necrotic pulmonary lesions upon Mycobacterium tuberculosis infection. BTZ-043 promoted significant reductions in lung and spleen bacterial burdens in the C3HeB/FeJ mouse model after 2 months of therapy. BTZ-043 penetrates cellular and necrotic lesions and was retained at levels above the serum-shifted minimal inhibitory concentration in caseum. The calculated rate of kill was found to be highest and dose-dependent during the second month of treatment. BTZ-043 treatment was associated with improved histology scores of pulmonary lesions, especially compared to control mice, which experienced advanced fulminant neutrophilic alveolitis in the absence of treatment. These positive treatment responses to BTZ-043 monotherapy in a mouse model of advanced pulmonary disease can be attributed to favorable distribution in tissues and lesions, retention in the caseum, and its high potency and bactericidal nature at drug concentrations achieved in necrotic lesions. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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