Improving the synthesis of hemin derivatives and their effect on bacterial biofilms

The emergence of antibiotic-resistant bacterial strains has recently resulted in a large focus on designing new antimicrobial agents, including those based on natural compounds. We have previously synthesized two disubstituted arginine-containing derivatives of hemin (HD) (4) and (5) that demonstrated pronounced antimicrobial activity against planktonic cells in vitro [1, 2]. These HDs are leading and promising for the creation of antibacterial agents on their basis. This research is aimed at improving the synthesis of HDs (4) and (5) to increase their yield, simplify the process and minimize the side reactions, as well as to establish their antimicrobial and destructive effect on biofilms, including those consisting of antibiotic-resistant bacteria. As a result, we were able to increase the yields of the protected dipeptide of ZArg(Z(2))SerNH(2) (3) and the corresponding HD (4) up to 97 and 93%, respectively, and also to minimize the side reaction of the formation of ornithine-containing HD. For the arginine amide modified HD (5), we have also proposed an improved synthesis scheme. The ability of HD to cause the bacteria death in the composition of formed biofilms, including those consisting of resistant bacteria, was shown. After the effect of HDs on the biofilm at concentrations of 80 and 100 mu g/ml, the CFU decrease was 3-5/ml. The fluorescent microscopy confirmed the bacteria mortality in the biofilm. Electron microscopy showed structural damage (fragmentation) of the formed bacterial biofilm under the effect of HDs.

Automated summary

The emergence of antibiotic-resistant bacterial strains has led to the focus on designing new antimicrobial agents. This study aimed to improve the synthesis of two compounds (HD) and determine their antimicrobial and destructive effects on biofilms, including those consisting of resistant bacteria.