Synthesis Characterization and Antibacterial Evaluation of Peptides and their Poly N Substituted Glycine Congeners

Abstract

With the emergence of multi drug resistant bacterial strains, it is the need of hour to develop new antimicrobial therapeutic agents which are less prone to development of resistance. Antimicrobial peptides have emerged as one such class of antimicrobials that have been proposed to be less prone to development of resistance due to their membrane disruptive action on bacteria. However antimicrobial peptides suffer from few limitations, like poor proteolytic stability and high cost of production. To overcome these limitations, poly-N-substituted glycines are usually designed and synthesized. In the present work, numerous peptides and their poly-N-substituted glycine congeners were synthesized and tested against various bacterial strains. Synthesized compounds exhibited minimum inhibitory concentration in micro molar range (3-100 and#956;g/ml) against bacterial strains tested. LP-23 and DP-23 emerged as lead compounds against M. smegmatis. On the other hand SA4 and SPO emerged as leads against biofilm forming susceptible and multidrug resistant clinical isolates of A. baumannii. These compounds have the potential to inhibit A. baumannii biofilms. All lead compounds LP-23, DP-23, SPO, and SA4 were found to be selective towards bacteria, as their HC50 values were high in comparison to their MIC values. The disruptive effects of lead compounds on bacterial cell membranes were visualized by SEM analysis. From the SEM microphotographs we could visualize disruptive effects of short peptide based compounds SA4 and SPO on cell membranes of A. baumannii cells. Similarly membrane disruption effects were also observed in DP-23 and LP-23 treated M. smegmatis cells, DP-23 was found to form pores on cell membranes. This non-specific membrane disruptive mode of action of these compounds makes them suitable candidates for antimicrobial drug development. In addition the stability of lead compounds to proteolysis was evaluated in human serum; SPO was found to be most stable in human serum. The present work affords four lead compounds LP-23,