Small Molecule Compounds Targeting the Bacterial Cell Wall for Bacterial Growth Inhibition

Aims: To determine the influence of molecular properties upon the effectiveness of four peptide compounds to inhibit growth of Escherichia coli and show the potential of small molecule peptide drugs.

Study Design: Examine molecular properties and extent of bacterial inhibition. Utilize numerical analysis to identify underlying relationships of molecular properties.

Place and Duration of Study: Department of Chemistry, University of Nebraska, Omaha, Nebraska, between January 2018 and April 2018.

Methodology: After studying the synthesis and evaluation of four compounds having amino acids substituent groups for their antibacterial activity, in vitro, the molecular properties were determined and analyzed by various methods of numerical analysis. The numerical methods included correlation, ANOVA, Grubb’s test, path analysis, and multiple regression. Two-dimensional plots revealed relationships among trends in molecular properties and bacterial growth inhibition.

Results: Compounds 1 and 2 have –D-alanine-D-alanine substituent covalently bonded to the carbonyl carbons of aspirin and nicotinic acid, respectively. Compounds 3 and 4 have –glycine-D-alanine-D-alanine substituent bonded to the carbonyl carbon of aspirin and ibuprofen, respectively. Rule of 5 indicated that all four compounds have favorable drug-likeness (i.e. zero violations of Rule of 5). The bioactivity evaluation indicated compounds 1, 2, 3, and 4 fall within the drug-likeness and biological activity of ion channel modulator, kinase inhibitor, protease inhibitor, GPCR ligand, and enzyme inhibitor. All four compounds showed significant growth inhibition of Escherichia coli, in vitro. Path analysis indicated that Log P, number of oxygen and nitrogen atoms, and number of rotatable bonds have highest causal relationship to the growth inhibition of bacteria.

Conclusion: Values of bioactivity and Rule of 5 showed that all compounds have favorable drug-likeness. Peptide-type compounds show promise for application in the clinical treatment of bacterial infections. This study provides evidence for which molecular properties are most important for the level of growth inhibition observed.