Novel Acyl Phosphate Mimics that Target PlsY, an Essential Acyltransferase in Gram‐Positive Bacteria

Abstract

PlsY is a recently discovered acyltransferase that executes an essential step in membrane phospholipid biosynthesis in Gram-positive bacteria. Using a bioisosteric replacement approach to generate substrate-based inhibitors of PlsY as potential novel antibacterial agents, a series of stabilized acylphosphate mimetics, including acylphosphonates, acyl αα,-difluoromethyl phosphonates, acyl phosphoramides, reverse amide phosphonates, acylsulfamates and acylsulfamides were designed and synthesized. Several acyl phosphonates, phosphoramides and sulfamates were identified as inhibitors of PlsY from Streptococcus pneumoniae and Bacillus anthracis. As anticipated, these inhibitors were competitive inhibitors with respect to the acylphosphate substrate. Antimicrobial testing showed the inhibitors to have generally weak anti Gram-positive activity with the exception of some acyl phosphonates, reverse amide phosphonates, and acylsulfamates that had potent activity against multiple strains of Bacillus anthracis.

Is bacterial fatty acid synthesis a valid target for antibacterial drug discovery?

“…The unique acyl-PO 4 intermediate is not found in mammals making the Gram-positive acyltransferase system a desirable target. One approach developed acyl-PO 4 analogs as potentially dual function product inhibitors PlsX and substrate inhibitors of PlsY [41], however, these hydrophobic molecules will need to be significantly improved before useful compounds will emerge. One strength of targeting these steps in lipid synthesis is that there are no mammalian PlsX/PlsY counterparts and acyltransferase inhibitors cannot be circumvented by supplementation with extracellular fatty acids.…”

Bacterial fatty acid metabolism in modern antibiotic discovery

“…In contrast, PlsY belongs to another protein family and uses acylphosphate made by PlsX for the acylation reaction [77]. Analogues of acyl-phosphate show that the on-target inhibition of PlsY inhibits bacterial growth [78,79]. However, current acylphosphate analogues are too hydrophobic to be “drug like”, and the lack of PlsY structure hampers improved compound design [78,79].…”

“…Analogues of acyl-phosphate show that the on-target inhibition of PlsY inhibits bacterial growth [78,79]. However, current acylphosphate analogues are too hydrophobic to be “drug like”, and the lack of PlsY structure hampers improved compound design [78,79]. Because PlsX catalyzes the reversible conversion between acyl-ACP and acyl-phosphate [80,81], acyl-phosphate analogues could be dual targeting inhibitors of PlsX and PlsY.…”

Tris(N-{bis[methyl(phenyl)amino]phosphoryl}benzenesulfonamidato-κ2O,O′)(1,10-phenanthroline-κ2N,N′)lanthanum(III)

“…Of special interest have been carbacylamidophosphates (CAPh), containing the functional fragment C(O)NHP(O), because of their properties as extractants (Morgalyuk et al, 2005;Safiulina et al, 2015), urease inhibitors (Jaroslav & Swerdloff, 1985), enzyme inhibitors (Grimes et al, 2008;Adams et al, 2002), their antibacterial properties (Oroujzadeh et al, 2017) and anticancer activity (Kovalchyk et al, 1991;Amirkhanov et al, 1995). The presence of the phosphoryl group gives them a high affinity towards highly charged metal ions, and these types of compounds are used in the coordination chemistry of lanthanides and actinides (Litsis et al, 2010(Litsis et al, , 2017Kariaka et al, 2013).…”