2 research outputs found
Charged Nonclassical Antifolates with Activity Against Gram-Positive and Gram-Negative Pathogens
Although
classical, negatively charged antifolates such as methotrexate
possess high affinity for the dihydrofolate reductase (DHFR) enzyme,
they are unable to penetrate the bacterial cell wall, rendering them
poor antibacterial agents. Herein, we report a new class of charged
propargyl-linked antifolates that capture some of the key contacts
common to the classical antifolates while maintaining the ability
to passively diffuse across the bacterial cell wall. Eight synthesized
compounds exhibit extraordinary potency against Gram-positive <i>S. aureus</i> with limited toxicity against mammalian cells
and good metabolic profile. High resolution crystal structures of
two of the compounds reveal extensive interactions between the carboxylate
and active site residues through a highly organized water network
Propargyl-Linked Antifolates are Dual Inhibitors of <i>Candida albicans</i> and <i>Candida glabrata</i>
Species of Candida, primarily <i>C. albicans</i> and
with increasing prevalence, <i>C. glabrata</i>, are responsible
for the majority of fungal bloodstream infections that cause morbidity,
especially among immune compromised patients. While the development
of new antifungal agents that target the essential enzyme, dihydrofolate
reductase (DHFR), in both Candida species would be ideal, previous
attempts have resulted in antifolates that exhibit inconsistencies
between enzyme inhibition and antifungal properties. In this article,
we describe the evaluation of pairs of propargyl-linked antifolates
that possess similar physicochemical properties but different shapes.
All of these compounds are effective at inhibiting the fungal enzymes
and the growth of <i>C. glabrata</i>; however, the inhibition
of the growth of <i>C. albicans</i> is shape-dependent with
extended para-linked compounds proving more effective than compact,
meta-linked compounds. Using crystal structures of DHFR from <i>C. albicans</i> and <i>C. glabrata</i> bound to lead
compounds, 13 new para-linked compounds designed to inhibit both species
were synthesized. Eight of these compounds potently inhibit the growth
of both fungal species with three compounds displaying dual MIC values
less than 1 μg/mL. Analysis of the active compounds shows that
shape and distribution of polar functionality is critical in achieving
dual antifungal activity