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- Title
Dynamic <sup>18</sup>F-Pretomanid PET imaging in animal models of TB meningitis and human studies.
- Authors
Mota, Filipa; Ruiz-Bedoya, Camilo A.; Tucker, Elizabeth W.; Holt, Daniel P.; De Jesus, Patricia; Lodge, Martin A.; Erice, Clara; Chen, Xueyi; Bahr, Melissa; Flavahan, Kelly; Kim, John; Brosnan, Mary Katherine; Ordonez, Alvaro A.; Peloquin, Charles A.; Dannals, Robert F.; Jain, Sanjay K.
- Abstract
Pretomanid is a nitroimidazole antimicrobial active against drug-resistant Mycobacterium tuberculosis and approved in combination with bedaquiline and linezolid (BPaL) to treat multidrug-resistant (MDR) pulmonary tuberculosis (TB). However, the penetration of these antibiotics into the central nervous system (CNS), and the efficacy of the BPaL regimen for TB meningitis, are not well established. Importantly, there is a lack of efficacious treatments for TB meningitis due to MDR strains, resulting in high mortality. We have developed new methods to synthesize 18F-pretomanid (chemically identical to the antibiotic) and performed cross-species positron emission tomography (PET) imaging to noninvasively measure pretomanid concentration-time profiles. Dynamic PET in mouse and rabbit models of TB meningitis demonstrates excellent CNS penetration of pretomanid but cerebrospinal fluid (CSF) levels does not correlate with those in the brain parenchyma. The bactericidal activity of the BPaL regimen in the mouse model of TB meningitis is substantially inferior to the standard TB regimen, likely due to restricted penetration of bedaquiline and linezolid into the brain parenchyma. Finally, first-in-human dynamic 18F-pretomanid PET in six healthy volunteers demonstrates excellent CNS penetration of pretomanid, with significantly higher levels in the brain parenchyma than in CSF. These data have important implications for developing new antibiotic treatments for TB meningitis. Pretomanid has been approved for use in cases of multi-drug resistant pulmonary tuberculosis, yet the penetration of this antibiotic into other target tissues is not well established. Authors provide insight on pretomanid pharmacokinetics in the central nervous system, using positron emission tomography in animal models, and human studies.
- Subjects
MULTIDRUG-resistant tuberculosis; TUBERCULOSIS; POSITRON emission tomography; MYCOBACTERIUM tuberculosis; ANIMAL models in research; MENINGITIS; CENTRAL nervous system
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-35730-3