TY - JOUR
T1 - Stable pantothenamide bioisosteres: novel antibiotics for Gram-positive bacteria
AU - Jansen, Patrick A.M.
AU - van der Krieken, Danique A.
AU - Botman, Peter N.M.
AU - Blaauw, Richard H.
AU - Cavina, Lorenzo
AU - Raaijmakers, Eline M.
AU - de Heuvel, Erik
AU - Sandrock, Julia
AU - Pennings, Lian J.
AU - Hermkens, Pedro H.H.
AU - Zeeuwen, Patrick L.J.M.
AU - Rutjes, Floris P.J.T.
AU - Schalkwijk, Joost
PY - 2019/9/1
Y1 - 2019/9/1
N2 - The emergence of multidrug resistant bacteria has prioritized the development of new antibiotics. N-substituted pantothenamides, analogs of the natural compound pantetheine, were reported to target bacterial coenzyme A biosynthesis, but these compounds have never reached the clinic due to their instability in biological fluids. Plasma-stable pantothenamide analogs could overcome these issues. We first synthesized a number of bioisosteres of the prototypic pantothenamide N7-Pan. A compound with an inverted amide bond (CXP18.6-012) was found to provide plasma-stability with minimal loss of activity compared to the parent compound N7-Pan. Next, we synthesized inverted pantothenamides with a large variety of side chains. Among these we identified a number of novel stable inverted pantothenamides with selective activity against Gram-positive bacteria such as staphylococci and streptococci, at low micromolar concentrations. These data provide future direction for the development of pantothenamides with clinical potential.
AB - The emergence of multidrug resistant bacteria has prioritized the development of new antibiotics. N-substituted pantothenamides, analogs of the natural compound pantetheine, were reported to target bacterial coenzyme A biosynthesis, but these compounds have never reached the clinic due to their instability in biological fluids. Plasma-stable pantothenamide analogs could overcome these issues. We first synthesized a number of bioisosteres of the prototypic pantothenamide N7-Pan. A compound with an inverted amide bond (CXP18.6-012) was found to provide plasma-stability with minimal loss of activity compared to the parent compound N7-Pan. Next, we synthesized inverted pantothenamides with a large variety of side chains. Among these we identified a number of novel stable inverted pantothenamides with selective activity against Gram-positive bacteria such as staphylococci and streptococci, at low micromolar concentrations. These data provide future direction for the development of pantothenamides with clinical potential.
U2 - 10.1038/s41429-019-0196-6
DO - 10.1038/s41429-019-0196-6
M3 - Article
C2 - 31171848
AN - SCOPUS:85067015968
SN - 0021-8820
VL - 72
SP - 682
EP - 692
JO - Journal of Antibiotics
JF - Journal of Antibiotics
IS - 9
ER -