Structure‐based drug design and in vitro testing reveal new inhibitors of enoyl‐acyl carrier protein reductases

Abstract

The need for new antibacterial agents is increasingly becoming of great importance as bacterial resistance to current drugs is quickly spreading. Enoyl‐acyl carrier protein reductases (FabI) are important enzymes for fatty acid biosynthesis in bacteria and other micro‐organisms. In this project, we conducted structure‐based virtual screening against the FabI enzyme, and accordingly, 37 compounds were selected for experimental testing. Interestingly, five compounds were able to demonstrate antimicrobial effect with variable inhibition activity against various strains of bacteria and fungi. Minimum inhibitory concentrations of the active compounds were determined and showed to be in low to medium micromolar range. Subsequently, enzyme inhibition assay was carried out for our five antimicrobial hits to confirm their biological target and determine their IC50 values. Three of these tested compounds exhibited inhibition activity for the FabI enzyme where our best hit MN02 had an IC50 value of 7.8 μM. Furthermore, MN02 is a small bisphenolic compound that is predicted to have all required features to firmly bind with the target enzyme. To sum up, hits discovered in this work can act as a good starting point for the future development of new and potent antimicrobial agents.

Molecular Modelling Study and Antibacterial Evaluation of Diphenylmethane Derivatives as Potential FabI Inhibitors

“…In comparison with our lead compound MN02 [ 24 ], RK09 and RK10 showed even greater potency against the Gram-positive strains (three-fold) with slightly lesser activity against E. coli ( Table 2 ). Compared to Chloramphenicol and TCL, all hits showed better inhibition against the MRSA strain, but much lesser or no activity against E. coli .…”

“…As part of our attempts to participate in the worldwide efforts combating the rapid spread of bacterial resistance, our team had identified MN02 as a promising lead FabI inhibitor and thus a potential antibacterial agent [ 24 ]. The lead optimization stage was initiated by searching the NCI (National Cancer Institute repository, Bethesda, MD, USA) ligand database [ 27 ] for new a set of derivatives or closely related structures, using a 2D search algorithm called the MACCS structural keys by molecular operating environment (MOE) software [ 28 ].…”

“…Currently, there are no FabI inhibitors in the drug market and therefore the discovery of new FabI inhibitors would provide additional alternatives for clinicians and other health care providers while combating bacterial infections. In our previous work [ 24 ], we have recently discovered a small FabI inhibitor “MN02”, which is a small bisphenolic compound that belongs to the diphenylmethane family and exhibits antibacterial activity in the low micromolar range, with a broad spectrum of activity. This compound has interesting similarities with the standard FabI inhibitor triclosan [ 25 ], especially in that it was predicted to bind in a similar fashion, forming the hydrogen bonding and stacking interactions with the key tyrosine residue and the cofactor nicotinamide ring [ 26 ].…”