TY - JOUR
T1 - Dynamic 18F-Pretomanid PET imaging in animal models of TB meningitis and human studies
AU - Mota, Filipa
AU - Ruiz-Bedoya, Camilo A.
AU - Tucker, Elizabeth W.
AU - Holt, Daniel P.
AU - De Jesus, Patricia
AU - Lodge, Martin A.
AU - Erice, Clara
AU - Chen, Xueyi
AU - Bahr, Melissa
AU - Flavahan, Kelly
AU - Kim, John
AU - Brosnan, Mary Katherine
AU - Ordonez, Alvaro A.
AU - Peloquin, Charles A.
AU - Dannals, Robert F.
AU - Jain, Sanjay K.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-35730-3
DO - 10.1038/s41467-022-35730-3
M3 - Article
C2 - 36581633
AN - SCOPUS:85145126140
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 7974
ER -