A Noncompetitive Inhibitor for <i>Mycobacterium
tuberculosis</i>’s Class IIa Fructose 1,6-Bisphosphate
Aldolase
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Abstract
Class
II fructose 1,6-bisphosphate aldolase (FBA) is an enzyme
critical for bacterial, fungal, and protozoan glycolysis/gluconeogenesis.
Importantly, humans lack this type of aldolase, having instead a class
I FBA that is structurally and mechanistically distinct from class
II FBAs. As such, class II FBA is considered a putative pharmacological
target for the development of novel antibiotics against pathogenic
bacteria such as <i>Mycobacterium tuberculosis</i>, the
causative agent for tuberculosis (TB). To date, several competitive
class II FBA substrate mimic-styled inhibitors have been developed;
however, they lack either specificity, potency, or properties that
limit their potential as possible therapeutics. Recently, through
the use of enzymatic and structure-based assisted screening, we identified 8-hydroxyquinoline carboxylic acid (HCA)
that has an IC<sub>50</sub> of 10 ± 1 μM for the class
II FBA present in <i>M. tuberculosis</i> (MtFBA). As opposed
to previous inhibitors, HCA behaves in a noncompetitive manner, shows
no inhibitory properties toward human and rabbit class I FBAs, and
possesses anti-TB properties.
Furthermore, we were able to determine the crystal structure of HCA
bound to MtFBA to 2.1 Å. HCA also demonstrates inhibitory effects
for other class II FBAs,
including pathogenic bacteria such as methicillin-resistant <i>Staphylococcus aureus</i>. With its broad-spectrum potential,
unique inhibitory characteristics,
and flexibility of functionalization, the HCA scaffold likely represents
an important advancement in the development of class II FBA inhibitors
that can serve as viable preclinical candidates