Synthetic Antibiotic Kills Bacteria and Prevents Biofilm Formation

The peptidomimetic compound HDM-4 (Host Defence Peptidomimetic 4) exhibits broad-spectrum antibacterial activity against Gram-negative bacteria and inhibits the formation of biofilms.

A peptidomimetic is a small protein-like molecular chain designed to mimic a peptide. They typically arise either from modification of an existing peptide, or by designing similar systems that mimic peptides, such as peptoids and beta-peptides. The altered chemical structure is designed to favor molecular properties increasing stability or biological activity. These modifications involve changes to the peptide that will not occur naturally (such as altered backbones or the incorporation of non-natural amino acids).

Investigators at the University of Copenhagen (Denmark) and their colleagues at the University of British Columbia (Canada) recently characterized HDM-4's mode of action against Gram-negative bacteria.

They reported in the October 10, 2013, issue of the journal Chemistry & Biology that HDM-4 generated holes in the outer membrane and partly depolarized the inner membrane at its minimal inhibitory concentration (MIC). In addition, HDM-4 rapidly became distributed within the bacterial cell at lethal concentrations that could bind to DNA.

The multimodal action of HDM-4 resulted in it being less likely to lead to resistance development as compared to single-target antibiotics. The compound exhibited multispecies anti-biofilm activity at sub-MIC levels. Furthermore, HDM-4 modulated the host's immune response by inducing the release of the chemoattractants interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and MCP-3 from human peripheral blood mononuclear cells. Additionally, the compound suppressed lipopolysaccharide-mediated inflammation by reducing the release of the proinflammatory cytokines IL-6 and tumor necrosis factor-alpha (TNF-alpha).

“We have succeeded in preparing and characterizing a very stable substance that kills multiresistant bacteria extremely quickly and effectively. The most interesting aspect is that the bacteria are attacked using a multifunctional mechanism that drastically reduces the risk of resistance development compared with traditional antibiotics,” said first author Dr. Rasmus Jahnsen, a researcher on drug design and pharmacology at the University of Copenhagen. “The killing mechanism involves destabilizing the bacterial membrane and binding onto the bacteria’s DNA, which in both cases results in the death of the bacteria. We have also shown that the substance can activate the human body’s own immune cells, strengthening its defense against bacteria during infection.”

“Only a tiny fraction of pharmaceutical research is devoted to development of new antibiotics — partly because research into cancer and chronic diseases such as diabetes and cardiovascular diseases are seen as better long-term investments. This leaves us in the extremely unfortunate situation where infectious diseases once again pose extremely serious threats to human health as the efficacy of medical drugs continues to be undermined by bacterial resistance. It is therefore important to conduct more research into new antibiotics,” said Dr. Jahnsen.

Related Links:
University of Copenhagen
University of British Columbia