TY - JOUR
T1 - Exploring fluorinated heptose phosphate analogues as inhibitors of HldA and HldE, key enzymes in the biosynthesis of lipopolysaccharide
AU - Cao, Jun
AU - Veytia Bucheli, Jose Ignacio
AU - Liang, Lina
AU - Wouters, Johan
AU - Silva-Rosero, Isabella
AU - Bussmann, Julie
AU - Gauthier, Charles
AU - De Bolle, Xavier
AU - Groleau, Marie Christine
AU - Déziel, Eric
AU - Vincent, Stéphane P.
N1 - Publisher Copyright:
© 2024 Elsevier Inc.
PY - 2024/12
Y1 - 2024/12
N2 - The growing threat of bacterial resistance to antibiotics has led to the rise of anti-virulence strategies as a promising approach. These strategies aim to disarm bacterial pathogens and improve their clearance by the host immune system. Lipopolysaccharide, a key virulence factor in Gram-negative bacteria, has been identified as a potential target for anti-virulence agents. In this study, we focus on inhibiting HldA and HldE, bacterial enzymes from the heptose biosynthesis pathway, which plays a key role in lipopolysaccharide biosynthesis. We present the synthesis of two fluorinated non-hydrolysable heptose phosphate analogues. Additionally, the inhibitory activity of a family of eight heptose phosphate analogues against HldA and HldE was assessed. This evaluation revealed inhibitors with affinities in the low μM range, with the most potent compound showing inhibition constant values of 15.4 μM for HldA and 16.9 μM for HldE. The requirement for a phosphate group at the C-7 position was deemed essential for inhibitory activity, while the presence of a hydroxy anomeric group was found to be beneficial, a phenomenon rationalized through computational modeling. Additionally, the introduction of a single fluorine atom α to the phosphonate moiety conferred a slight advantage for inhibition. These findings suggest that mimicking the structure of D-glycero-β-D-manno-heptose 1,7-bisphosphate, the product of the phosphorylation step in heptose biosynthesis, could be a promising strategy to disrupt this biosynthetic pathway. In terms of the in vivo effects, these heptose phosphate analogues neither demonstrated significant LPS-disrupting effects nor exhibited growth inhibitory activity on their own. Additionally, they did not alter the susceptibility of bacteria to hydrophobic antibiotics. The highly charged nature of these molecules may hinder their ability to penetrate the bacterial cell wall. To overcome this limitation, alternative strategies such as incorporating protecting groups that facilitate their entry and can subsequently be cleaved within the bacterial cytoplasm could be explored.
AB - The growing threat of bacterial resistance to antibiotics has led to the rise of anti-virulence strategies as a promising approach. These strategies aim to disarm bacterial pathogens and improve their clearance by the host immune system. Lipopolysaccharide, a key virulence factor in Gram-negative bacteria, has been identified as a potential target for anti-virulence agents. In this study, we focus on inhibiting HldA and HldE, bacterial enzymes from the heptose biosynthesis pathway, which plays a key role in lipopolysaccharide biosynthesis. We present the synthesis of two fluorinated non-hydrolysable heptose phosphate analogues. Additionally, the inhibitory activity of a family of eight heptose phosphate analogues against HldA and HldE was assessed. This evaluation revealed inhibitors with affinities in the low μM range, with the most potent compound showing inhibition constant values of 15.4 μM for HldA and 16.9 μM for HldE. The requirement for a phosphate group at the C-7 position was deemed essential for inhibitory activity, while the presence of a hydroxy anomeric group was found to be beneficial, a phenomenon rationalized through computational modeling. Additionally, the introduction of a single fluorine atom α to the phosphonate moiety conferred a slight advantage for inhibition. These findings suggest that mimicking the structure of D-glycero-β-D-manno-heptose 1,7-bisphosphate, the product of the phosphorylation step in heptose biosynthesis, could be a promising strategy to disrupt this biosynthetic pathway. In terms of the in vivo effects, these heptose phosphate analogues neither demonstrated significant LPS-disrupting effects nor exhibited growth inhibitory activity on their own. Additionally, they did not alter the susceptibility of bacteria to hydrophobic antibiotics. The highly charged nature of these molecules may hinder their ability to penetrate the bacterial cell wall. To overcome this limitation, alternative strategies such as incorporating protecting groups that facilitate their entry and can subsequently be cleaved within the bacterial cytoplasm could be explored.
KW - Anti-virulence
KW - Fluorine
KW - Heptose phosphate analogues
KW - HldA
KW - HldE
KW - Lipopolysaccharide
UR - http://www.scopus.com/inward/record.url?scp=85203023222&partnerID=8YFLogxK
U2 - 10.1016/j.bioorg.2024.107767
DO - 10.1016/j.bioorg.2024.107767
M3 - Article
C2 - 39241584
AN - SCOPUS:85203023222
SN - 0045-2068
VL - 153
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
M1 - 107767
ER -