Tissue distribution of doxycycline in animal models of tuberculosis.

Tissue distribution of doxycycline in animal models of tuberculosis. Antimicrob Agents Chemother. 2020 Feb 10;: Authors: Gengenbacher M, Zimmerman MD, Sarathy JP, Kaya F, Wang H, Mina M, Carter C, Hossen MA, Su H, Trujillo C, Ehrt S, Schnappinger D, Dartois V Abstract Doxycycline, an FDA-approved tetracycline, is used in tuberculosis in vivo models for the temporal control of mycobacterial gene expression. In these models, animals are infected with recombinant Mycobacterium tuberculosis carrying genes of interest under transcriptional control of the doxycycline responsive TetR-tetO unit. To minimize fluctuations of plasma levels, doxycycline is usually administered in the diet. However, tissue penetration studies to identify the minimum doxycycline content in food achieving complete repression of TetR-controlled genes in TB infected organs and lesions have not been conducted. Here, we first determined the tetracycline concentrations required to achieve silencing of M. tuberculosis target genes in vitro. Next, we measured doxycycline concentrations in plasma, major organs and lung lesions, in TB infected mice and rabbits, and compared these values to silencing concentrations measured in vitro. We found that 2,000 ppm doxycycline supplemented in mouse and rabbit feed is sufficient to reach target concentrations in TB lesions. In rabbit chow, the calcium content had to be reduced 5-fold to minimize chelation of doxycycline and deliver a...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research