TY - JOUR
T1 - Small-Molecule Probes Reveal Esterases with Persistent Activity in Dormant and Reactivating Mycobacterium tuberculosis
AU - Tallman, Katie R.
AU - Levine, Samantha R.
AU - Beatty, Kimberly E.
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/12/9
Y1 - 2016/12/9
N2 - Mycobacterium tuberculosis (Mtb) is the deadliest bacterial pathogen in the world. An estimated one-third of humans harbor Mtb in a dormant state. These asymptomatic, latent infections impede tuberculosis eradication due to the long-term potential for reactivation. Dormant Mtb has reduced enzymatic activity, but hydrolases that remain active facilitate pathogen survival. We targeted Mtb esterases, a diverse set of enzymes in the serine hydrolase family, and studied their activities using both activity-based probes (ABPs) and fluorogenic esterase substrates. These small-molecule probes revealed functional esterases in active, dormant, and reactivating cultures. Using ABPs, we identified five esterases that remained active in dormant Mtb, including LipM (Rv2284), LipN (Rv2970c), CaeA (Rv2224c), Rv0183, and Rv1683. Three of these, CaeA, Rv0183, and Rv1683, were catalytically active in all three culture conditions. Fluorogenic probes additionally revealed LipH (Rv1399c), Culp1 (Rv1984c), and Rv3036c esterase activity in dormant and active cultures. Esterases with persistent activity are potential diagnostic biomarkers or therapeutic targets for Mtb-infected individuals with latent or active tuberculosis.
AB - Mycobacterium tuberculosis (Mtb) is the deadliest bacterial pathogen in the world. An estimated one-third of humans harbor Mtb in a dormant state. These asymptomatic, latent infections impede tuberculosis eradication due to the long-term potential for reactivation. Dormant Mtb has reduced enzymatic activity, but hydrolases that remain active facilitate pathogen survival. We targeted Mtb esterases, a diverse set of enzymes in the serine hydrolase family, and studied their activities using both activity-based probes (ABPs) and fluorogenic esterase substrates. These small-molecule probes revealed functional esterases in active, dormant, and reactivating cultures. Using ABPs, we identified five esterases that remained active in dormant Mtb, including LipM (Rv2284), LipN (Rv2970c), CaeA (Rv2224c), Rv0183, and Rv1683. Three of these, CaeA, Rv0183, and Rv1683, were catalytically active in all three culture conditions. Fluorogenic probes additionally revealed LipH (Rv1399c), Culp1 (Rv1984c), and Rv3036c esterase activity in dormant and active cultures. Esterases with persistent activity are potential diagnostic biomarkers or therapeutic targets for Mtb-infected individuals with latent or active tuberculosis.
KW - Mycobacterium tuberculosis
KW - chemical biology
KW - esterase
KW - fluorescent
KW - proteomics
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U2 - 10.1021/acsinfecdis.6b00135
DO - 10.1021/acsinfecdis.6b00135
M3 - Article
C2 - 27690385
AN - SCOPUS:85003766042
SN - 2373-8227
VL - 2
SP - 936
EP - 944
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 12
ER -